Thiadiazoline derivative

ABSTRACT

(wherein R 1  and R 4  are the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted lower alkenyl, or the like; R 6  represents a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, or the like; R 2  represents —C(═W)R 6  or the like; R 3  represents a hydrogen atom, —C(═W A )R 6A , or the like) 
     Antitumor agents which comprises a thiadiazoline derivative represented by the aforementioned general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient are provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of application Ser. No. 12/098,736, filed Apr. 7, 2008, which is a divisional of application Ser. No. 10/497,531, which is a National Stage Application of International Application No. PCT/JP02/12961, filed Dec. 11, 2002, which was not published in English under PCT Article 21(2), entering the National Stage on Jun. 10, 2004, and which claims priority of Japanese Application Nos. 2001-377456, filed Dec. 11, 2001 and 2002-237399, filed Aug. 16, 2002. The entire disclosures of application Ser. Nos. 10/497,531 and 12/098,736 are considered as being part of this application, and the entire disclosures of application Ser. Nos. 10/497,531 and 12/098,736 are expressly incorporated by reference herein in their entireties.

TECHNICAL FIELD

The present invention relates to an antitumor agent comprising a thiadiazoline derivative or a pharmacologically acceptable salt thereof as an active ingredient, and a thiadiazoline derivative or a pharmacologically acceptable salt thereof which is useful for therapeutic treatment of a tumor.

BACKGROUND ART

In chemotherapies of cancers, a variety of anticancer agents including antimitotic agents such as taxane and vinca alkaloid, topoisomerase inhibitors, alkylating agents and the like have been used. These agents have side effects such as bone marrow toxicity and neuropathy, a problem of drug resistance and the like. Therefore, novel anticancer agents which have improvement in the above problems have so far been desired.

It is known that thiadiazoline derivatives have inhibitory activity against transcription factor STAT6 activation, antagonistic action of integrin, and the control of insect or acarid pests (Japanese Published Unexamined Patent Application No. 2000-229959, WO01/56994, U.S. Pat. No. 6,235,762). In addition, it is known that the derivatives have antibacterial activity, ACE inhibitory activity and the like [J. Bangladesh Chem. Soc., Vol. 5, p. 127 (1992), WO93/22311, Japanese Published Unexamined Patent Application No. 62-53976 (1987)].

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a thiadiazoline derivative or a pharmacologically acceptable salt thereof which is useful for therapeutic treatment of a human malignant tumor, for example, breast cancer, gastric cancer, ovarian cancer, colon cancer, lung cancer, brain tumor, laryngeal cancer, hematological cancer, urinary or genital tumor including bladder cancer and prostatic cancer, renal cancer, skin carcinoma, hepatic carcinoma, pancreatic cancer, a uterine cancer, or the like. Another object of the present invention is to provide an antitumor agent comprising a thiadiazoline derivative or a pharmacologically acceptable salt thereof as an active ingredient.

The present invention relates to the following (1) to (43).

(1) An antitumor agent which comprises a thiadiazoline derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient

<wherein

-   R¹ and R⁴ are the same or different and each represents

a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocyclic group, or substituted or unsubstituted aryl;

-   R² represents

a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted cycloalkyl,

—C(═W)R⁶ [wherein

-   -   W represents         -   an oxygen atom or a sulfur atom     -   R⁶ represents         -   a hydrogen atom, substituted or unsubstituted lower alkyl,             substituted or unsubstituted lower alkenyl, substituted or             unsubstituted cycloalkyl, a substituted or unsubstituted             aryl, a substituted or unsubstituted heterocyclic group,         -   —NR⁷R⁸ (wherein             -   R⁷ and R⁸ are the same or different and each represents                 -   a hydrogen atom, substituted or unsubstituted lower                     alkyl, substituted or unsubstituted lower alkenyl,                     substituted or unsubstituted cycloalkyl, substituted                     or unsubstituted aryl, or a substituted or                     unsubstituted heterocyclic group, or             -   R⁷ and R⁸ are combined together with the adjacent                 nitrogen atom to form a substituted or unsubstituted                 heterocyclic group),         -   —OR⁹ (wherein             -   R⁹ represents                 -   substituted or unsubstituted lower alkyl,                     substituted or unsubstituted lower alkenyl,                     substituted or unsubstituted cycloalkyl, or                     substituted or unsubstituted aryl) or         -   —SR¹⁰ (wherein             -   R¹⁰ represents                 -   substituted or unsubstituted lower alkyl,                     substituted or unsubstituted lower alkenyl, or                     substituted or unsubstituted aryl)]

—NR¹¹R¹² (wherein

-   -   R¹¹ and R¹² are the same or different and each represents         -   a hydrogen atom, substituted or unsubstituted lower alkyl,             substituted or unsubstituted lower alkenyl, substituted or             unsubstituted cycloalkyl, or         -   —C(═O)R¹³ [wherein             -   R¹³ represents                 -   substituted or unsubstituted lower alkyl,                     substituted or unsubstituted lower alkenyl,                     substituted or unsubstituted aryl, a substituted or                     unsubstituted heterocyclic group,                 -   —NR^(7A)R^(8A) (wherein R^(7A) and R^(8A) have the                     same meanings as those of the aforementioned R⁷ and                     R⁸, respectively), or                 -   —OR^(9A) (wherein R^(9A) has the same meaning as                     that of the aforementioned R⁹)]) or

—SO₂R¹⁴ (wherein

-   -   R¹⁴ represents         -   substituted or unsubstituted lower alkyl, substituted or             unsubstituted lower alkenyl, substituted or unsubstituted             aryl, or a substituted or unsubstituted heterocyclic group),             or

-   R¹ and R² are combined together with the adjacent nitrogen atom to     form a substituted or unsubstituted heterocyclic group,

-   R⁶ represents

substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocyclic group, or substituted or unsubstituted aryl, or

-   R⁴ and R⁵ are combined together to represent

—(CR²⁸R²⁹)_(m1)-Q-(CR^(28A)R^(29A))_(m2)— {wherein

-   -   Q represents         -   a single bond, substituted or unsubstituted phenylene, or             cycloalkylene,     -   m1 and m2 are the same or different and each represents an         integer of from 0 to 4, with the proviso that m1 and m2 are not         0 at the same time,     -   R²⁸, R²⁹, R^(28A) and R^(29A) are the same or different and each         represents a hydrogen atom, substituted or unsubstituted lower         alkyl,         -   —OR³⁰ [wherein             -   R³⁰ represents                 -   a hydrogen atom,                 -   substituted or unsubstituted lower alkyl,                 -   substituted or unsubstituted lower alkenyl,                 -   —CONR³¹R³² (wherein                 -    R³¹ and R³² are the same or different and each                     represents                 -    a hydrogen atom, substituted or unsubstituted lower                     alkyl, a substituted or unsubstituted heterocyclic                     group, or substituted or unsubstituted aryl),                 -   —SO₂NR³³R³⁴ (wherein                 -    R³³ and R³⁴ are the same or different and each                     represents                 -    a hydrogen atom, substituted or unsubstituted lower                     alkyl, a substituted or unsubstituted heterocyclic                     group, or substituted or unsubstituted aryl), or                 -   —COR³⁵ (wherein                 -    R³⁵ represents                 -    a hydrogen atom, substituted or unsubstituted lower                     alkyl, a substituted or unsubstituted heterocyclic                     group, or substituted or unsubstituted aryl)],         -   —NR³⁶R³⁷ [wherein             -   R³⁶ and R³⁷ are the same or different and each                 represents                 -   a hydrogen atom,                 -   substituted or unsubstituted lower alkyl,                 -   —COR³⁸ (wherein                 -    R³⁸ represents                 -    a hydrogen atom, substituted or unsubstituted lower                     alkyl, a substituted or unsubstituted heterocyclic                     group, substituted or unsubstituted aryl,                     substituted or unsubstituted lower alkoxy,                     substituted or unsubstituted aryloxy, amino,                     substituted or unsubstituted lower alkylamino,                     substituted or unsubstituted di(lower alkyl)amino,                     or substituted or unsubstituted arylamino), or                 -   —SO₂R³⁸ (wherein                 -    R³⁹ represents                 -    substituted or unsubstituted lower alkyl, a                     substituted or unsubstituted heterocyclic group, or                     substituted or unsubstituted aryl)], or         -   —CO₂R⁴⁰ (wherein             -   R⁴⁰ represents                 -   a hydrogen atom, substituted or unsubstituted lower                     alkyl, or substituted or unsubstituted aryl), and

when m1 or m2 is an integer of 2 or more, each R²⁸, R²⁹, R^(28A) and R^(29A) may be the same or different, respectively, and any two of R²⁸, R²⁹, R^(28A) and R^(29A) which are bound to the adjacent two carbon atoms may be combined to form a bond}, and

-   R³ represents

a hydrogen atom or

—C(═W^(A))R^(6A) (wherein W^(A) and R^(6A) have the same meanings as those of the aforementioned W and R⁶, respectively)>.

(2) The antitumor agent according to the aforementioned (1), wherein R⁴ is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocyclic group, or substituted or unsubstituted aryl, and R⁵ is substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocyclic group, or substituted or unsubstituted aryl, or R⁴ and R⁵ are combined to represent —(CR²⁸R²⁹)_(m1)-Q-(CR^(28A)R^(29A))_(m2)—.

(3) The antitumor agent according to the aforementioned (1), wherein R⁵ is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted lower alkenyl, or substituted or unsubstituted cycloalkyl.

(4) The antitumor agent according to the aforementioned (1) or (2), wherein R⁵ is substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group.

(5) The antitumor agent according to the aforementioned (1) or (2), wherein R⁵ is substituted or unsubstituted phenyl, or substituted or unsubstituted thienyl.

(6) The antitumor agent according to any one of the aforementioned (1) to (5), wherein R⁴ is substituted or unsubstituted lower alkyl.

(7) The antitumor agent according to the aforementioned (1), wherein R⁴ and R⁵ are combined to represent —(CR²⁸R²⁹)_(m1)-Q-(CR^(28A)R^(29A))_(m2)—,

(8) The antitumor agent according to the aforementioned (1), wherein R⁴ and R⁵ are combined to represent —(CH₂)_(m1)-Q-(CH₂)_(m2)—.

(9) The antitumor agent according to the aforementioned (7) or (8), wherein Q is substituted or unsubstituted phenylene.

(10) The antitumor agent according to any one of the aforementioned (1) to (9), wherein R¹ is a hydrogen atom, or substituted or unsubstituted lower alkyl.

(11) The antitumor agent according to any one of the aforementioned (1) to (9), wherein R¹ is a hydrogen atom.

(12) The antitumor agent according to any one of the aforementioned (1) to (11), wherein R² is —C(═W)R⁶.

(13) The antitumor agent according to the aforementioned (12), wherein R⁶ is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted lower alkenyl, or substituted or unsubstituted cycloalkyl.

(14) The antitumor agent according to the aforementioned (12) or (13), wherein W is an oxygen atom.

(15) The antitumor agent according to any one of the aforementioned (1) to (9), wherein R¹ and R² are combined to form a substituted or unsubstituted heterocyclic group together with the adjacent nitrogen atom.

(16) The antitumor agent according to any one of the aforementioned (1) to (15), wherein R³ is —C(═W^(A))R^(6A).

(17) The antitumor agent according to the aforementioned (16), wherein R^(6A) is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted lower alkenyl, or substituted or unsubstituted cycloalkyl.

(18) The antitumor agent according to the aforementioned (16), wherein R^(6A) is lower alkyl.

(19) The antitumor agent according to any one of the aforementioned (16) to (18), wherein W^(A) is an oxygen atom.

(20) A thiadiazoline derivative represented by the general formula (IA) or a pharmacologically acceptable salt thereof:

{wherein R^(1A), R^(2A), R^(3A), R^(4A) and R^(5A) have the same meanings as those of the aforementioned R¹, R², R³, R⁴ and R⁵, respectively, with the proviso that when R^(2A) and R^(2A) are the same to be —CONHR^(8B) (wherein R^(8B) represents a substituted or unsubstituted lower alkyl, or substituted or unsubstituted aryl), and

(i) R^(4A) is a hydrogen atom, or

(ii) one of R^(4A) and R^(5A) is substituted or unsubstituted lower alkyl, then the other of R^(4A) and R^(5A) only represents substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, or substituted or unsubstituted lower alkynyl

[provided that

-   -   (a) when R^(1A), R^(2A) and R^(3A) are hydrogen atoms, and one         of R^(4A) and R^(5A) is methyl,         -   the other of R^(4A) and R^(5A) is not any of phenyl,             4-nitrophenyl, 4-aminophenyl, 4-bromophenyl, 3-nitrophenyl             and 4-methoxy-3-nitrophenyl,     -   (b) when R^(1A) and R^(2A) are hydrogen atoms, R^(3A) is acetyl,         -   (i) and one of R^(4A) and R^(5A) is methyl,             -   the other of R^(4A) and R^(5A) is not any of methyl,                 ethyl, phenyl, 4-methoxyphenyl,                 2-naphthylsulfonylmethyl, 4-bromophenylsulfonylmethyl                 and 4-chlorophenylsulfonylmethyl, and         -   (ii) and R^(4A) is a hydrogen atom,             -   R^(5A) is not any of phenyl, 4-nitrophenyl,                 4-chlorophenyl, 4-methoxyphenyl, 4-dimethylaminophenyl                 and pyridyl,     -   (c) when R^(1A) is a hydrogen atom, R^(2A) and R^(3A) are         acetyl,         -   (i) and one of R^(4A) and R^(5A) is methyl,             -   the other of R^(4A) and R^(5A) is not any of methyl,                 ethyl, propyl, butyl, hexyl, heptyl, phenyl, benzyl,                 acetylmethyl, tert-butoxycarbonylmethyl,                 ethoxycarbonylmethyl, 4-bromophenylsulfonylmethyl,                 4-bromophenylsulfonylethyl,                 4-chlorophenylsulfonylmethyl,                 3,4-dichlorophenylsulfonylmethyl,                 3,4-dichlorophenylsulfonylethyl,                 3,4-dimethylphenylsulfonylmethyl, phenylsulfonylmethyI,                 4-methylphenylsulfonylmethyl,                 4-methylphenylsulfonylethyl,                 4-(acetylamino)phenylsulfonylethyl,                 4-bromophenylsulfonylethyl,                 2-(4-methylphenylsulfonyl)-2-phenylethyl,                 2-(4-methylphenylthio)-2-phenylethyl,                 2-naphthylsulfonylethyl, 2-naphthylsulfonylmethyl,                 phenethyl, 3-benzoyloxyphenyl,                 2-oxo-2H-1-benzopyran-3-yl, 2-furyl, 5-nitro-2-furyl,                 5-methyl-2-furyl, 2-thienyl, 5-chloro-2-thienyl,                 3-acetoxyphenyl, 3-nitrophenyl, 4-nitrophenyl,                 4-fluorophenyl, 3-acetylaminophenyl, 4-methoxyphenyl,                 3-methoxyphenyl, 4-ethylphenyl, 4-methylphenyl,                 4-bromophenyl, 4-nonyloxyphenyl, 4-phenyiphenyl,                 3,4-dimethoxyphenyl, 1,3-benzodioxol-5-yl,                 4-(benzimidazol-2-ylamino)phenyl,                 4-(1-methylbenzimidazol-2-ylamino)phenyl, 3-pyridyl,                 2-naphthyl,                 2-acetylamino-4-acetyl-1,3,4-thiadiazolin-5-yl and                 4-acetylaminophenylsulfonylmethyl,         -   (ii) and one of R^(4A) and R^(5A) is phenyl,             -   the other of R^(4A) and R^(5A) is not any of phenyl,                 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-nitrophenyl,                 ethoxycarbonylmethyl, isobutyl, sec-butyl, n-butyl and                 acetylaminomethyl,         -   (iii) and one of R^(4A) and R^(6A) is 2-acetoxyphenyl,             -   the other of R^(4A) and R^(5A) is not 2-phenylethenyl;         -   (iv) and R^(4A) is a hydrogen atom or 4-methoxyphenyl,             -   R^(5A) is not 4-methoxyphenyl,         -   (v) and R^(4A) is a hydrogen atom,             -   R^(5A) is not any of phenyl, 4-nitrophenyl,                 4-chlorophenyl, 4-dimethylaminophenyl and pyridyl,         -   (vi) and R^(4A) and R^(5A) are combined to represent             -   —(CH₂)_(m1)-Q-(CH₂)_(m2)— (wherein m1, m2 and Q have the                 same meanings as those of the aforementioned,                 respectively),                 -   —(CH₂)_(m1)-Q-(CH₂)_(m2)— wherein Q is a single bond                     and the sum of m1 and m2 is 5, is excluded         -   (vii) and one of R^(4A) and R^(5A) is             1,2,3-triacetoxypropyl,             -   the other of R^(4A) and R^(5A) is not                 3,4-dihydro-3-oxo-2-quinoxalinyl, and         -   (viii) and one of R^(4A) and R^(5A) is ethyl,             -   the other of R^(4A) and R^(5A) is not ethyl,     -   (d) when R^(1A) and R^(4A) are hydrogen atoms, and         -   (i) R^(2A) and R^(3A) are the same to be propionyl or             benzoyl or         -   (ii) R^(2A) is propionyl and R^(3A) is acetyl,             -   R^(5A) is not phenyl,     -   (e) when R^(1A) and R^(3A) are hydrogen atoms,         -   R^(2A) is acetyl, and         -   one of R^(4A) and R^(5A) is methyl,             -   the other of R^(4A) and R^(5A) is not either of phenyl                 and 3,4-dichlorophenylsulfonylethyl,     -   (f) when R^(1A) is phenyl, R^(2A) and R^(3A) are acetyl,         -   (i) and one of R^(4A) and R^(5A) is methyl,             -   the other of R^(4A) and R^(5A) is not either of                 4-acetoxy-6-methyl-2-oxo-2H-pyran-3-yl and                 2-oxo-2H-1-benzopyran-3-yl, and         -   (ii) and R^(4A) is phenyl,             -   R^(5A) is not phenyl,     -   (g) when R^(1A) is methyl, R^(2A) and R^(3A) are acetyl,         -   (i) and R^(4A) is a hydrogen atom,             -   R^(5A) is not phenyl,         -   (ii) and one of R^(4A) and R^(5A) is methyl,             -   the other of R^(4A) and R^(5A) is not either of                 ethoxycarbonylethyl and ethoxycarbonylpropyl,     -   (h) when R^(1A), R^(2A) and R^(4A) are methyl, and         -   R^(5A) is pyridyl,             -   R^(3A) is not —COR^(c) (wherein R^(c) represents methyl,                 chloromethyl, methoxy, ethoxycarbonylmethyl or                 ethoxycarbonylethenyl),     -   (j) when one of R^(1A) and R^(2A) is a hydrogen atom,         -   the other of R^(1A) and R^(2A) is ethyl, and R^(3A) is a             hydrogen atom or acetyl,             -   R^(4A) and R^(5A) are not methyl at the same time,     -   (k) when R^(1A) is 4-chlorophenyl,         -   R^(2A) is a hydrogen atom, and         -   one of R^(4A) and R^(5A) is methyl,             -   the other of R^(4A) and R^(5A) is not                 (1-methylbenzimidazol-2-ylamino)phenyl, and R^(3A) is                 not acetyl,     -   (m) when R^(1A) is phenyl, 4-chlorophenyl, 4-methylphenyl or         -   4-methoxyphenyl,         -   R^(2A) is a hydrogen atom, and         -   R^(4A) and R^(5A) are methyl,             -   R^(3A) is not any of acetyl, 4-chlorophenoxyacetyl,                 2-chlorophenoxyacetyl, 3-methylphenoxyacetyl and                 phenylaminocarbonyl,     -   (n) when R^(2A) and R^(3A) are acetyl,         -   one of R^(4A) and R^(5A) is methyl,         -   (i) and the other of R^(4A) and R^(5A) is             1H-benzotriazol-1-ylmethyl,             -   R^(1A) is not any of cyclohexyl, benzyl, phenyl,                 2-methylphenyl and 4-methoxyphenyl,         -   (ii) and the other of R^(4A) and R^(5A) is             2-methylbenzimidazol-1-ylmethyl or             2-ethylbenzimidazol-1-ylmethyl,             -   R^(1A) is not any of cyclohexyl, phenyl and                 4-bromophenyl,     -   (o) when R^(1A) is a hydrogen atom,         -   R^(2A) is acetyl, and         -   R^(4A) and R^(5A) are methyl,             -   R^(3A) is not benzoyl,     -   (p) when one of R^(1A) and R^(2A) is hydrogen atom,         -   the other of R^(1A) and R^(2A) is methyl, and         -   R^(4A) and R^(5A) are both methyl or both ethyl,             -   R^(3A) is not any of acetyl, benzoyl, pivaloyl,                 3-nitrobenzoyl, 2-fluorobenzoyl, 4-fluorobenzoyl,                 2-trifluoromethylbenzoyl and 3-trifluoromethylbenzoyl,                 and     -   (q) when R^(1A) is methyl,         -   R^(2A) is methylaminocarbonyl, and         -   R^(4A) and R^(5A) are both methyl or both ethyl,             -   R^(3A) is not any of acetyl, benzoyl, pivaloyl,                 2-fluorobenzoyl, 4-fluorobenzoyl,                 2-trifluoromethylbenzoyl, 3-trifluoromethylbenzoyl and                 4-trifluoromethylbenzoyl]}.

(21) The thiadiazoline derivative according to the aforementioned (20), wherein R^(4A) is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkynyl, or substituted or unsubstituted lower alkenyl, R^(5A) is substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocyclic group, or substituted or unsubstituted aryl, or R^(4A) and R^(5A) are combined to represent —(CR²⁸R²⁹)_(m1)-Q-(CR²⁸R^(29A))_(m2)— (wherein R²⁸, R²⁹, R^(28A), R^(29A), m1, m2 and Q have the same meanings as those of the aforementioned, respectively), or the pharmacologically acceptable salt thereof.

(22) The antitumor agent according to the aforementioned (20), wherein R^(5A) is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted lower alkenyl, or substituted or unsubstituted cycloalkyl.

(23) The thiadiazoline derivative according to the aforementioned (20) or (21), wherein R^(5A) is substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group, or the pharmacologically acceptable salt thereof.

(24) The thiadiazoline derivative according to the aforementioned (20) or (21), wherein R^(5A) is substituted or unsubstituted phenyl or substituted or unsubstituted thienyl, or the pharmacologically acceptable salt thereof.

(25) The thiadiazoline derivative according to any one of the aforementioned (20) to (24), wherein R^(4A) is substituted or unsubstituted lower alkyl, or the pharmacologically acceptable salt thereof.

(26) The thiadiazoline derivative according to any one of the aforementioned (20) to (24), wherein R^(4A) is substituted lower alkyl, or the pharmacologically acceptable salt thereof.

(27) The thiadiazoline derivative according to the aforementioned (20), wherein R^(4A) and R^(5A) combine together to represent —(CR²⁸R²⁹)_(m1)-Q-(CR^(28A)R^(29A))_(m2)— (wherein R²⁸, R²⁹, R^(28A), R^(29A), m1 , m2, and Q have the same meanings as those of the aforementioned, respectively), or the pharmacologically acceptable salt thereof.

(28) The thiadiazoline derivative according to the aforementioned (20), wherein R^(4A) and R^(5A) are combined to represent —(CH₂)_(m1)-Q-(CH₂)_(m2)— (wherein m1, m2 and Q have the same meanings as those of the aforementioned, respectively), or the pharmacologically acceptable salt thereof.

(29) The thiadiazoline derivative according to the aforementioned (27) or (28), wherein Q is substituted or unsubstituted phenylene, or the pharmacologically acceptable salt thereof.

(30) The thiadiazoline derivative according to any one of the aforementioned (20) to (29), wherein R^(1A) is a hydrogen atom, or substituted or unsubstituted lower alkyl, or the pharmacologically acceptable salt thereof.

(31) The thiadiazoline derivative according to any one of the aforementioned (20) to (29), wherein R^(1A) is a hydrogen atom, or the pharmacologically acceptable salt thereof.

(32) The thiadiazoline derivative according to any one of the aforementioned (20) to (31), wherein R^(2A) is —C(═W)R⁶ (wherein W and R⁶ have the same meanings as those of the aforementioned, respectively), or the pharmacologically acceptable salt thereof.

(33) The thiadiazoline derivative according to the aforementioned (32), wherein R⁶ is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted lower alkenyl, or substituted or unsubstituted cycloalkyl, or the pharmacologically acceptable salt thereof.

(34) The thiadiazoline derivative according to the aforementioned (32) or (33), wherein W is an oxygen atom, or the pharmacologically acceptable salt thereof.

(35) The thiadiazoline derivative according to any one of the aforementioned (20) to (29), wherein R^(1A) and R^(2A) are combined together with the adjacent nitrogen atom to form a substituted or unsubstituted heterocyclic group, or the pharmacologically acceptable salt thereof.

(36) The thiadiazoline derivative according to any one of the aforementioned (20) to (35), wherein R^(3A) is —C(═W^(A))R^(6A) (wherein W^(A) and R^(6A) have the same meanings as those of the aforementioned, respectively), or the pharmacologically acceptable salt thereof.

(37) The thiadiazoline derivative according to the aforementioned (36), wherein R^(6A) is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted lower alkenyl, or substituted or unsubstituted cycloalkyl, or the pharmacologically acceptable salt thereof.

(38) The thiadiazoline derivative according to the aforementioned (36), wherein R^(6A) is lower alkyl, or the pharmacologically acceptable salt thereof.

(39) The thiadiazoline derivative according to any one of the aforementioned (36) to (38), wherein W^(A) is an oxygen atom, or the pharmacologically acceptable salt thereof.

(40) A pharmaceutical composition which comprises the thiadiazoline derivative according to any one of the aforementioned (20) to (39) or a pharmacologically acceptable salt thereof as an active ingredient.

(41) An antitumor agent which comprises the thiadiazoline derivative according to any one of the aforementioned (20) to (39) or a pharmacologically acceptable salt thereof as an active ingredient.

(42) Use of the thiadiazoline derivative according to any one of the aforementioned (20) to (39) or a pharmacologically acceptable salt thereof for the manufacture of an antitumor agent.

(43) A method for the treatment of malignant tumor comprising administering an effective amount of the thiadiazoline derivative according to any one of the aforementioned (20) to (39) or a pharmacologically acceptable salt thereof.

Hereinafter, compounds represented by the general formulae (I) and (IA) are referred to as Compound (I) and Compound (IA), respectively. The compounds having the other formula numbers are referred to in the same manner.

In the definition of each group of Compound (I) and Compound (IA),

(i) examples of the lower alkyl moiety in the lower alkyl, the lower alkoxy, the lower alkylamino and the di(lower alkylamino include straight or branched chain alkyl having 1 to 10 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like.

The two lower alkyl moieties in the di(lower alkylamino may be the same or different.

(ii) Examples of the cycloalkyl include cycloalkyl having 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

Examples of the cycloalkylene include cycloalkylene having 3 to 8 carbon atoms, for example, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene and the like.

(iii) Examples of the lower alkenyl include straight or branched chain alkenyl having 2 to 8 carbon atoms, for example, vinyl, allyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and the like.

(iv) Examples of the lower alkynyl include straight or branched chain alkynyl having 2 to 8 carbon atoms, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl and the like.

(v) Examples of the aryl moiety in the aryl, the aryloxy and the arylamino include phenyl, naphthyl and the like.

(vi) Examples of the heterocyclic group include an aliphatic heterocyclic group, an aromatic heterocyclic group and the like. Examples of the aliphatic heterocyclic group include a 5- or 6-membered monocyclic aliphatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and a bicyclic or tricyclic condensed aliphatic heterocyclic group comprising 3- to 8-membered rings and containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and the like, for example, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidino, morpholino, oxazolinyl, dioxolanyl, tetrahydropyranyl and the like. Examples of the aromatic heterocyclic group include a 5- or 6-membered monocycle aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and a bicycle or tricyclic condensed aromatic heterocyclic group comprising 3- to 8-membered rings and containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and the like, for example, furyl, thienyl, benzothienyl, pyrrolyl, pyridyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, ozadiazolyl, pyrimidinyl, indolyl, isoindolyl, benzothiazolyl, benzimidazolyl, benzotriazolyl, quinolyl, isoquinolyl, quinazolinyl, pyranyl and the like.

(vii) Examples of the heterocyclic group formed together with the adjacent nitrogen atom include an aliphatic heterocyclic group containing at least one nitrogen atom, and the like. Said aliphatic heterocyclic group containing at least one nitrogen atom may contain an oxygen atom, a sulfur atom or another nitrogen atom, and examples thereof include, for example, pyrrolidinyl, morpholino, thiomorpholino, pyrazolidinyl, piperidino, piperazinyl, homopiperazinyl, aziridinyl, azetidinyl, azolidinyl, perhydroazepinyl, perhydroazocinyl, succinimidyl, pyrrolidonyl, glutarimidyl, piperidonyl and the like.

(viii) The substituents in the substituted lower alkyl, the substituted lower alkoxy, the substituted lower alkenyl, the substituted lower alkynyl, the substituted cycloalkyl, the substituted lower alkylamino, and the substituted di(lower alkylamino may be the same or different and include for example, 1 to 3 substituent(s), such as halogen, oxo, hydroxy, nitro, aside, cycloalkyl, aryl, a heterocyclic group, substituted aryl (the substituent in said substituted aryl has the same meaning as that of the after-mentioned substituent (xii) in the substituted aryl), a substituted heterocyclic group (the substituent in said substituted heterocyclic group has the same meaning as that of the after-mentioned substituent (xiii) in the substituted heterocyclic group), —CONR¹⁵R¹⁶ <wherein

R¹⁵ and R¹⁶ are the same or different and each represents

-   -   a hydrogen atom, hydroxy, cycloalkyl, lower alkyl,     -   lower alkenyl, aryl, a heterocyclic group,     -   substituted aryl (the substituent in said substituted aryl has         the same meaning as that of the after-mentioned         substituent (xii) in the substituted aryl),     -   a substituted heterocyclic group (the substituent in said         substituted heterocyclic group has the same meaning as that of         the after-mentioned substituent (xiii) in the substituted         heterocyclic group) or     -   substituted lower alkyl {in said substituted lower alkyl, the         substituents are the same or different and 1 to 3         substituent(s), such as         -   hydroxy, lower alkoxy, oxo, carboxy,         -   lower alkoxycarbonyl, an aryl, a heterocyclic group,         -   —CONR^(15A)R^(16A) [wherein             -   R^(15A) and R^(16A) are the same or different and each                 represents                 -   a hydrogen atom, hydroxy, lower alkyl, or                 -   substituted lower alkyl (in said substituted lower                     alkyl, the substituents (a) are the same or                     different and 1 to 3 substituent(s), such as                     hydroxy, lower alkoxy, oxo, carboxy, lower                     alkoxycarbonyl, aryl, a heterocyclic group, amino,                     lower alkylamino, di(lower alkyl)amino and the                     like), or             -   R^(15A) and R^(16A) are combined to form a heterocyclic                 group             -   together with the adjacent nitrogen atom],         -   —NR⁴¹R⁴² [wherein             -   R⁴¹ and R⁴² are the same or different and each                 represents                 -   a hydrogen atom, lower alkyl,                 -   lower alkanoyl, aroyl, aryl,                 -   a heterocyclic group,                 -   substituted lower alkyl (the substituent in said                     substituted lower alkyl has the same meaning as that                     of the aforementioned substituent (a) in the                     substituted lower alkyl),                 -   a substituted lower alkanoyl (in said substituted                     lower alkanoyl, the substituents (b) are the same or                     different and 1 to 3 substituent(s), such as                     hydroxy, lower alkoxy, oxo, carboxy, lower                     alkoxycarbonyl, amino, lower alkylamino, di(lower                     alkyl)amino and the like),                 -   substituted aroyl (the substituent in said                     substituted aroyl has the same meaning as that of                     the aforementioned substituent (b) in the                     substituted lower alkanoyl),                 -   substituted aryl (the substituent in said                     substituted aryl has the same meaning as that of the                     after-mentioned substituent (xii) in the substituted                     aryl) or                 -   a substituted heterocyclic group (the substituent in                     said substituted heterocyclic group has the same                     meaning as that of the after-mentioned                     substituent (xiii) in the substituted heterocyclic                     group), or             -   R⁴¹ and R⁴² are combined to form a heterocyclic group or                 a substituted heterocyclic group together with the                 adjacent nitrogen atom (the substituent in said                 substituted heterocyclic group formed together with the                 adjacent nitrogen atom has the same meaning as that of                 the after-mentioned substituent (xiii) in the                 substituted heterocyclic group formed together with the                 adjacent nitrogen atom)]), or

R¹⁵ and R¹⁶ are combined to form a heterocyclic group or a substituted heterocyclic group together with the adjacent nitrogen atom (the substituent in said substituted heterocyclic group formed together with the adjacent nitrogen atom has the same meaning as that of the after-mentioned substituent (xiii) in the substituted heterocyclic group formed together with the adjacent nitrogen atom)>, —CO₂R²⁶ (wherein

R²⁶ represents

-   -   a hydrogen atom, lower alkyl, cycloalkyl, lower alkenyl,     -   lower alkynyl, aryl,     -   substituted aryl (the substituent in said substituted aryl has         the same meaning as that of the after-mentioned         substituent (xii) in the substituted aryl), or     -   substituted lower alkyl [in said substituted lower alkyl, the         substituents (c) are the same or different and 1 to 3         substituent(s), such as         -   hydroxy, halogen, lower alkoxy, oxo, carboxy,         -   lower alkoxycarbonyl, aryl, a heterocyclic group,         -   —CONR^(15B)R^(16B) (wherein R^(15B) and R^(16B) have the             same meanings as those of the aforementioned R¹⁵ and R¹⁶,             respectively),         -   —NR^(41A)R^(42A) (wherein R^(41A) and R^(42A) have the same             meanings as those of the aforementioned R⁴¹ and R⁴²,             respectively), and the like]}, —COR^(26A) (wherein R^(26A)             has the same meaning as that of the aforementioned R²⁶),

-   —NR¹⁷R¹⁸ <wherein

R¹⁷ and R¹⁸ are the same or different and each represents

-   -   a hydrogen atom, lower alkyl, lower alkenyl, aroyl,     -   aryl, a heterocyclic group, cycloalkyl,     -   aralkyloxycarbonyl,     -   substituted lower alkyl (in said substituted lower alkyl, the         substituents (d) are the same or different and 1 to 3         substituent(s), such as         -   hydroxy, lower alkoxy, oxo, carboxy,         -   lower alkoxycarbonyl, aryl, a heterocyclic group,         -   substituted aryl (the substituent in said substituted aryl             has the same meaning as that of the after-mentioned             substituent (xii) in the substituted aryl),         -   a substituted heterocyclic group (the substituent in said             substituted heterocyclic group has the same meaning as that             of the after-mentioned substituent (xiii) in the substituted             heterocyclic gram),         -   —O(CH₂CH₂O)_(n)R¹⁹ (wherein n represents an integer of from             1 to 15, and R¹⁹ represents lower alkyl),         -   —CONR^(15C)R^(16C) (wherein R^(15C) and R^(16C) have the             same meanings as those of the aforementioned R¹⁵ and R¹⁶,             respectively),         -   —SO₂R²⁴ [wherein             -   R²⁴ represents                 -   lower alkyl, arylor                 -   substituted aryl (the substituent in said                     substituted aryl has the same meaning as that of the                     after-mentioned substituent (xii) in the substituted                     aryl)],         -   —NR^(41B)R^(42B) (wherein R^(41B) and R^(42B) have the same             meanings as those of the aforementioned R⁴¹ and R⁴²,             respectively), and the like},     -   substituted aryl (the substituent in said substituted aryl has         the same meaning as that of the after-mentioned         substituent (xii) in the substituted aryl),     -   a substituted heterocyclic group (the substituent in said         substituted heterocyclic group has the same meaning as that of         the after-mentioned substituent (xiii) in the substituted         heterocyclic group),     -   —COR^(26B) {wherein         -   R^(26B) represents             -   lower alkyl, lower alkenyl, lower alkynyl,             -   aryl,             -   substituted lower alkyl (the substituent in said                 substituted lower alkyl has the same meaning as that of                 the aforementioned substituent (c) in the substituted                 lower alkyl),             -   substituted aryl (the substituent in said substituted                 aryl has the same meaning as that of the after-mentioned                 substituent (xii) in the substituted aryl),             -   —NR^(26C)R^(26D) (wherein R^(26C) and R^(26D) are the                 same or different, and each has the same meaning as-that                 of the aforementioned R²⁶) or             -   —OR²⁷ [wherein                 -   R²⁷ represents                 -    lower alkyl, aryl,                 -    substituted lower alkyl (the substituent in said                     substituted lower alkyl has the same meaning as that                     of the aforementioned substituent (c) in the                     substituted lower alkyl) or                 -    substituted aryl (the substituent in said                     substituted aryl has the same meaning as that of the                     after-mentioned substituent (xii) in the substituted                     aryl)]), or     -   —SO₂R^(26E) (wherein R^(26E) has the same meaning as that of the         aforementioned R²⁶), or

R¹⁷ and R¹⁸ are combined to form a heterocyclic group or a substituted heterocyclic group together with the adjacent nitrogen atom (the substituent in said substituted heterocyclic group formed together with the adjacent nitrogen atom has the same meaning as that of the after-mentioned substituent (xiii) in the substituted heterocyclic group formed together with the adjacent nitrogen atom)>, —N⁺R²⁰R²¹R²²X— (wherein

R²⁰ and R²¹ are the same or different and each represents lower alkyl, or R²⁰ and R²¹ are combined to form a heterocyclic group together with the adjacent nitrogen atom,

R²² represents lower alkyl, and

X represents each atom of chlorine, bromine or iodine),

-   —OR²³ {wherein

R²³ represents

-   -   lower alkyl, cycloalkyl, aryl, a heterocyclic group,     -   substituted aryl (the substituent in said substituted aryl has         the same meaning as that of the after-mentioned         substituent (xii) in the substituted aryl),     -   a substituted heterocyclic group (the substituent in said         substituted heterocyclic group has the same meaning as that of         the after-mentioned substituent (xiii) in the substituted         heterocyclic group),     -   substituted lower alkyl [in said substituted lower alkyl, the         substituents (e) are the same or different and 1 to 3         substituent(s), such as         -   hydroxy, halogen, lower alkoxy, oxo, carboxy,         -   lower alkoxycarbonyl, aryl, a heterocyclic group,         -   substituted aryl (the substituent in said substituted aryl             has the same meaning as that of the after-mentioned             substituent (xii) in the substituted aryl),         -   a substituted heterocyclic group (the substituent in said             substituted heterocyclic group has the same meaning as that             of the after-mentioned substituent (xiii) in the substituted             heterocyclic group),         -   —O(CH₂CH₂O)_(nA)R^(19A) (wherein nA and R^(19A) have the             same meanings as those of the aforementioned n and R¹⁹,             respectively),             -   —CONR^(15D)R^(16D) (wherein R^(15D) and R^(16D) have the                 same meanings as those of R¹⁵ and R¹⁶, respectively),         -   —NR^(41C)R^(42C) (wherein R^(41C) and R^(42C) have the same             meanings as those of the aforementioned R⁴¹ and R⁴²,             respectively) and the like],     -   —COR^(26F) (wherein R^(26F) has the same meaning as that of the         aforementioned R²⁶) or     -   —CONR^(15E)R^(16E) (wherein R^(15E) and R^(16E) have the same         meanings as those of the aforementioned R¹⁵ and R¹⁶,         respectively)),

-   —SR^(23A) (wherein R^(23A) has the same meaning as that of the     aforementioned R²³), —SO₂R²⁵ [wherein

R²⁵ represents

-   -   lower alkyl, cycloalkyl, aryl,     -   substituted lower alkyl (the substituent in said substituted         lower alkyl has the same meaning as that of the aforementioned         substituent (c) in the substituted lower alkyl),     -   a substituted aryl (the substituent in the substituted aryl has         the same meaning as that of the after-mentioned         substituent (xii) in the substituted aryl), or     -   —NR^(16F)R^(16F) (wherein R^(15F) and R^(16F) have the same         meanings as those of the aforementioned R¹⁵ and R¹⁶,         respectively)],         —OSO₂R^(25A) (wherein R^(25A) has the same meaning as that of         the aforementioned R²⁵), and the like.

Herein, the lower alkyl moiety in the lower alkyl, the lower alkoxy, the lower alkoxycarbonyl, the lower alkylamino and the di(lower alkylamino, the aryl moiety in the aryl and the aroyl, the cycloalkyl, the lower alkenyl, the lower alkynyl, the heterocyclic group, and the heterocyclic group formed together with the adjacent nitrogen atom have the same meanings as those of the aforementioned lower alkyl (i), aryl (v), cycloalkyl (ii), lower alkenyl (iii), lower alkynyl (iv), heterocyclic group (vi) and a heterocyclic group formed together with the adjacent nitrogen atom (vii), respectively. Also, the lower alkyl moiety in the lower alkanoyl mentioned here has the same meaning as that of the aforementioned lower alkyl (i), the halogen (ix) represents each atom of fluorine, chlorine, bromine and iodine, and examples of the aralkyl moiety (xi) in the aralkyloxycarbonyl include aralkyl having 7 to 15 carbon atoms, for example, benzyl, phenethyl, benzhydryl, naphthylmethyl and the like.

(xii) The substituents in the substituted aryl, the substituted aryloxy, the substituted arylamino and the substituted phenylene may be the same or different and 1 to 3 substituent(s), such as

halogen, lower alkyl, nitro, oxo, hydroxy, lower alkoxy, amino, lower alkylamino, di(lower alkyl)amino, lower alkylaminocarbonyloxy, di(lower alkyl)aminocarbonyloxy, lower alkanoyl, lower alkanoylamino, lower alkanoyloxy, aryl, arylsulfonyl, heterocyclic amino, aroyl, carboxy, lower alkoxycarbonyl, cyano, methylenedioxy,

substituted lower alkyl (in said substituted lower alkyl, the substituents (f) are the same or different and 1 to 3 substituent(s), such as halogen, oxo, carboxy, lower alkoxycarbonyl, amino, lower alkylamino, di(lower alkyl)amino, hydroxy, lower alkoxy and the like),

substituted arylsulfonyl (the substituent in said substituted arylsulfonyl has the same meaning as that of the aforementioned substituent (f)),

substituted heterocyclic amino (the substituent in said substituted heterocyclic amino has the same meaning as that of the aforementioned substituent (f)) and the like.

the lower alkyl moiety in the lower alkyl, the lower alkylamino, the di(lower alkylamino, the lower alkylaminocarbonyloxy, the di(lower alkyl)aminocarbonyloxy (the two lower alkyl moieties in said di(lower alkyl)aminocarbonyloxy may be the same or different), the lower alkoxycarbonyl and the lower alkoxy, the heterocyclic moiety in the heterocyclic amino, the aryl moiety in the aryl, the arylsulfonyl and the aroyl, and the halogen have the same meanings as those of the aforementioned lower alkyl (i), heterocyclic group (vi), aryl (v) and halogen (ix), respectively. Also, examples of the lower alkanoyl moiety (x) in the lower alkanoyl, the lower alkanoylamino and the lower alkanoyloxy which are noted here include a straight or branched chain alkanoyl having 2 to 9 carbon atoms, for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, nonanoyl and the like.

(xiii) Examples of the substituent-in the substituted heterocyclic group and the substituted heterocyclic group formed together with the adjacent nitrogen atom include oxo and the like as well as the aforementioned groups mentioned in the definition of the substituent (xii) in the substituted aryl.

Example of the pharmacologically acceptable salt of Compound (I) and Compound (IA) include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like. Examples of the acid addition salt include an inorganic salt such as a hydrochloride, a sulfate and a phosphate, an organic acid salt such as an acetate, a maleate, a fumarate, a tartrate, a citrate, a lactate, an aspartate, a glutamate, succinate and the like. Examples of the metal salt include an alkali metal salt such as a sodium salt and a potassium salt, an alkaline-earth metal salt such as a magnesium salt and a calcium salt, an aluminium salt, a zinc salt and the like. Examples of the ammonium salt include a salt of ammonium, tetramethylammonium and the like. Examples of the organic amine addition salt include an addition salt with morpholine, piperidine or the like. Examples of the amino acid addition salt include an addition salt with lysine, glycine, phenylalanine and the like.

Next, the methods of preparing the Compound (I) and the Compound (IA) are described as follows.

In the preparing methods as shown below, when the defined group changes under the conditions of the method carried out, or the method is inappropriate for carrying out, the desired compound can be obtained by using the protection and deprotection of the groups which are ordinarily used in the synthetic organic chemistry [e.g., Protective Groups in Organic Synthesis, T. W. Greene, John Wiley & Sons Inc. (1981)] and the like. In addition, the order of the steps for introducing a substituent and the like may be changed, if necessary.

Compound (I) can be prepared according to the following reaction steps.

Compound (IA) can also be prepared in the similar manner as in the preparing methods of Compound (I) as shown below.

Preparing Method 1

Among Compound (I), Compound (Ia) wherein R² is a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted lower alkenyl, or substituted or unsubstituted cycloalkyl, or R¹ and R² are combined to form a substituted or unsubstituted heterocyclic group together with the adjacent nitrogen atom, and R³ is —C(═O)R^(6A) can be obtained from Compound (II) and Compound (III), via Compound (IV), in accordance with known methods [e.g., J. Heterocyclic Chem., Vol. 21, p. 599 (1984) and the like]:

(wherein R¹, R⁴, R⁵, R⁶ and R^(6A) have the same meanings as those mentioned above, respectively, X¹ has the same meaning as that of the aforementioned X, and R^(2a) represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted lower alkenyl, or substituted or unsubstituted cycloalkyl among the definition of the aforementioned R², or R¹ and R^(2a) are combined to form a substituted or unsubstituted heterocyclic group together with the adjacent nitrogen atom.) Preparing Method 2

Among Compound (I), Compound (Ib) wherein R² and R³ are the same to be —C(═O)R^(6B) (wherein R^(6B) has the same meaning as that of the aforementioned R⁶) can be obtained from Compound (IVa) among Compound (IV) prepared by the preparing method 1 wherein R^(2a) is a hydrogen atom, and Compound (Va) or Compound (Vb) in accordance with known methods [e.g., J. Bangladesh Chem. Soc., Vol. 5, p. 127 (1992), J. Org. Chem., Vol. 45, p. 1473 (1980), Patent of East. Germany No. 243930, and the like]:

(wherein R¹, R⁴, R⁵ and R^(6B) have the same meanings as those mentioned above, respectively.) Preparing Method 3

Among Compound (Ia), Compound (Ic) wherein R² is a hydrogen atom and R⁸ is —C(═O)R^(6A) can be obtained by the following step from Compound (Ib) prepared by the Preparing method 2:

(wherein R¹, R⁴, R⁶, R^(6A) and R^(6B) have the same meanings as those mentioned above, respectively.)

Compound (Ic) can be obtained by treatment of Compound (Ib) in an inert solvent, for example, N,N-dimethylformamide and the like, in the presence of an appropriate base such as sodium hydride and the like, at a temperature between 0° C. and 80° C. for 10 minutes to 10 hours. The base is preferably used in an amount of 1 to 5 equivalents to Compound (Ib).

Alternatively, Compound (Ic) can also be obtained by the following method.

Compound (Ic) can be obtained by treatment of Compound (Ib) in an inert solvent, for example, aqueous or anhydrous ethanol, acetonitrile, chloroform and the like, in the presence of an appropriate base such as hydrazine monohydrate, aqueous sodium hydroxide and the like, at a temperature between 0° C. and 50° C. for 1 to 10 hours. The base is preferably used in an amount of 2 to 10 equivalents to Compound (Ib).

Compound (Ic) can also be obtained by the following method.

Compound (Ic) can be obtained by treatment of Compound (Ib) in a solvent such as methanol, tert-butanol and the like, in the presence of a reducing agent such as sodium borohydride and the like, and if necessary, in the presence of cerium chloride heptahydrate and the like, at a temperature between −10° C. and 100° C. for 0.1 to 15 hours. The reducing agent is preferably used in an amount of 1 to 200 equivalents to Compound (Ib).

Preparing Method 4

Among Compound (I), Compound (Ie) wherein R² is —C(═O)R⁶ and R³ is —C(═O)R^(6A) can be obtained by the following step from Compound (Ic) obtained by the Preparing method 1 or 3.

(wherein R¹, R⁴, R⁵, R⁶ and R^(6A) have the same meanings as those mentioned above, respectively, and X² has the same meaning as that of the aforementioned X.)

Compound (Ie) can be obtained by allowing Compound (Ic) to react with Compound (VA) or Compound (VB) in an inert solvent, for example, acetone, ethyl acetate, acetonitrile, N,N-dimethylformamide, dichloromethane and the like, in the presence of an appropriate base such as pyridine, 4-(dimethylamino)pyridine (DMAP), sodium hydride and the like, at a temperature between 0° C. and 120° C. for 2 to 12 hours. The base and Compound (VA) or Compound (VB) are preferably used, respectively, in an amount of 1 to 3 equivalents to Compound (Ic).

Preparing Method 5

Among Compound (I), Compound (If) wherein R² is —SO₂R¹⁴ and R³ is —C(═O)R^(6A) can be obtained from Compound (Ic) prepared by the Preparing method 1 or 3 in accordance with the method described in for example, Shin-Jikken-Kagaku-Koza (New Experiment Chemistry Lecture) Vol. 14, p. 1803 (Maruzen. 1978):

(wherein R¹, R⁴, R⁵, R^(6A) and R¹⁴ have the same meanings as those mentioned above, respectively, and X³ has the same meaning as that of the aforementioned X.) Preparing Method 6

Among Compound (I), Compound (Ig) wherein R² is —NR¹¹R¹² and R³ is —C(═O)R^(6A) can be obtained from Compound (VII) prepared in accordance with the method described in Indian J. Chem., Section B, Vol. 31(B), p. 547 (1992) in accordance with the methods described in for example, Indian J. Chem., Section B, Vol. 31B(8), p. 547 (1992), Phosphorus Sulfur & Silicon & the Related Elements, Vol. 122, p. 307 (1997) and the like,:

(wherein R¹, R⁴, R⁵, R^(6A), R¹¹ and R¹² have the same meanings as those mentioned above, respectively.) Preparing Method 7

Among Compound (Ie), Compound (Ie-b) wherein R¹ is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted lower alkenyl, or substituted or unsubstituted cycloalkyl can be obtained by the following step from Compound (Ie-a) among Compound (Ie) wherein R¹ is a hydrogen atom prepared by the Preparing method 4:

(wherein R⁴, R⁵, R⁶ and R^(6A) have the same meanings as those mentioned above, respectively, X⁴ has the same meaning as that of the aforementioned X, and R^(1a) represents substituted or unsubstituted lower alkyl,a substituted or unsubstituted lower alkynyl, substituted or unsubstituted lower alkenyl, or substituted or unsubstituted cycloalkyl among the definition of the aforementioned R¹.)

Compound (Ie-b) can be obtained by allowing Compound (Ie-a) to react with Compound (VIII) in an inert solvent, for example, N,N-dimethylformamide and the like, in the presence of an appropriate base such as sodium hydroxide, at a temperature between 0° C. and room temperature for 1 to 24 hours. The base and Compound (VIII) are preferably used in amounts of 2 to 5 equivalents and 2 to 3 equivalents, respectively, to Compound (Ie-a).

Preparing Method 8

Among Compound (I), Compound (Ih) wherein R³ is a hydrogen atom can be obtained by the methods described in for example, Phosphorus, Sulfur and Silicone and the Related Elements, Vol. 122, p. 307 (1997) and Chem. Ber., Vol. 123, p. 691 (1990) and the like, or the methods similar to the aforementioned methods.

Preparing Method 9

Among Compound (I), Compound (Ij) wherein R² and/or R² is —C(═S)R⁶ and/or —C(═S)R^(6A), respectively, can be obtained by thiocarbonylation of Compound (Ik) wherein the corresponding R² and/or R³ is —C(═O)R⁶ and/or —C(═O)R^(6A), respectively, among Compound (Ia) to Compound (Ih) obtained by the aforementioned the Preparing methods 1 to 7.

For example, Compound (Ij) can be obtained by treatment of Compound (Ik) in a solvent such as toluene and tetrahydrofuran, with an appropriate thiocarbonylating agent such as 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphophethane-2,4-disulfide (Lawesson's reagent), phosphorus pentasulfide and the like, at a temperature between room temperature and the boiling point of the solvent for 1 to 24 hours. The thiocarbonylating agent is preferably used in an amount of 2 to 10 equivalents to Compound (Ik).

Preparing Method 10

Among Compound (I), Compound (Im) wherein R³ is —C(═O)R^(6A) and R¹ and R^(2f) are combined to form a substituted or unsubstituted heterocyclic group together with the adjacent nitrogen atom can be obtained by the following step from Compound (In) wherein R¹ and R^(2a) are hydrogen atoms among Compound (Ia) prepared by the Preparing method 1, or from Compound (In) wherein R¹ is a hydrogen atom among Compound (Ic) prepared by the Preparing method 3:

(wherein R⁴, R⁵ and R^(6A) have the same meanings as those mentioned above, respectively, X⁵ has the same meaning as that of the aforementioned X, R^(1b) and R^(2b) represent a substituted or unsubstituted heterocyclic group formed together with the adjacent nitrogen atom, said heterocyclic group formed together with the adjacent nitrogen atom has the same meaning as that of the aforementioned heterocyclic group (vii) formed together with the adjacent nitrogen atom, and the substituent in said substituted heterocyclic group formed together with the adjacent nitrogen atom has the same meaning as that of the aforementioned substituent (xiii) in the heterocyclic group.)

Compound (Ip) can be obtained from Compound (In) by the methods described in for example, Chem. Commun., Vol. 8, p. 873 (1998) and the like, or the methods similar to the aforementioned methods.

Compound (Im) can be obtained by allowing Compound (Ip) to react with Compound (IX) in an inert solvent, for example, dichloromethane and the like, at a temperature between 0° C. and 60° C. for 10 minutes to 24 hours. Compound (IX) is preferably used in an amount of 2 to 50 equivalents to Compound (Ip).

Alternatively, Compound (Im) can also be obtained from Compound (Ie-c) wherein R¹ is a hydrogen atom and R⁶ is an alkyl group substituted with carboxyl group among Compound (Ie) prepared by the Preparing method 4 by the method described in for example, Synthesis-Stuttgart, Vol. 5, p. 420 (1991) or the methods similar to the aforementioned method.

Moreover, Compound (Im) can also be obtained from Compound (Ie-d) wherein R¹ is a hydrogen atom and R⁶ is an alkyl group substituted with halogen among Compound (Ie) by the method described in for example, Shin-Jikken-Kagaku-Koza (New Experiment Chemistry Lecture) Vol. 14, p. 1174 (Maruzen, 1978) and the like, or the methods similar to the aforementioned methods.

Furthermore, among Compound (I), Compound (Ij-a) wherein R³ is —C(═S)R^(6A) and R¹ and R² are combined to form a substituted or unsubstituted heterocyclic group together with the adjacent nitrogen atom can be obtained from Compound (Im) in the similar manner as the aforementioned the Preparing method 9.

In Compound (I), conversion of the functional group contained in R¹, R², R³, R⁴ or R⁵ can also be carried out by the aforementioned steps, or also by the other known methods (e.g., Comprehensive Organic Transformations, R. C. Larock (1989) and the like].

Compound (I) having the desired functional group at the desired position can be obtained by carrying out the aforementioned methods in appropriate combination.

The intermediates and the objective compounds in the aforementioned preparation methods can be purified and isolated by conducting a purification method ordinarily used in the synthetic organic chemistry such as filtration, extraction, washing, drying, concentration, recrystallization, various chromatography such as high performance liquid chromatography, thin layer chromatography, silica gel chromatography and the like. The intermediates can also be subjected to the next reaction without particular purification.

Some compounds among Compounds (I) may exist as position isomers, geometrical isomers, optical isomers, tautomers and the like. All possible isomers including the aforementioned isomers and mixtures thereof can be used for the antitumor agent of the present invention.

To obtain a salt of Compound (I), when Compound (I) obtained as a salt form, it may be purified as it is. When Compound (I) obtained as a free form, it may be dissolved or suspended in an appropriate solvent, and added with an appropriate acid or base to form a salt and then be isolated.

In addition, Compound (I) or a pharmacologically acceptable salt thereof may exist in the form of adducts with water or variety of solvents, which also can be used for the antitumor agent of the present invention.

Specific examples of Compound (IA) obtained by the present invention are shown in Tables 1 to 10. However, the compounds of the present invention are not limited to these examples.

The compounds shown in Tables 1 to 10 are used for the antitumor agent of the present invention, and other than the compounds, specific examples of compounds used in the present invention are shown in Tables 11 to 13. However, the compound used in the present invention is not limited to these examples.

TABLE 1 (IA-i)

Ex- Com- ample pound No. No. R^(1A) R^(2A) R^(4A) 2 2 —H —COCH₃ —CH₂CH₃ 4 4 —H —COCH₃ —CH(CH₃)₂ 5 5 —H —COCH₃

7 7 —CH₃ —COCH₃ —CH₃ 8 8 —CH₂CH₃ —CH₂CH₃ —CH₃ 8 9 —CH₂CH₃ —COCH₃ —CH₃ 9 10 —(CH₂)₂CH₃ —(CH₂)₂CH₃ —CH₃ 9 11 —(CH₂)₂CH₃ —COCH₃ —CH₃ 129 136 —H —CO₂C(CH₃)₃ —CH₃ 130 137 —H —CON(CH₃)₂ —CH₃ 131 138

—CH₃ 132 139

—CH₃ 133 140 —H —CO(CH₂)₄CH₃ —CH₂NHSO₂CH₃ 134 141 —H —COCH═CHCH₃ —CH₂NHSO₂CH₃ 135 142 —H

—CH₂NHSO₂CH₃ 136 143 —H —COC(CH₃)₂OCOCH₃ —CH₂NHSO₂CH₃ 137 144 —H —COC(CH₃)₂OH —CH₂NHSO₂CH₃ 138 145 —H —COCH₂OCH₃ —CH₂NHSO₂CH₃ 139 146 —H —COCH₂Cl —CH₂NHSO₂CH₃ 140 147 —H —COCH₂N(CH₃)₂ —CH₂NHSO₂CH₃ 141 148 —H —CO(CH₂)₃CO₂CH₃ —CH₂NHSO₂CH₃ 142 149 —H —CO(CH₂)₃CO₂H —CH₂NHSO₂CH₃ 143 150

—CH₂NHSO₂CH₃ 144 151 —H —CO(CH₂)₃Br —CH₂NHSO₂CH₃ 145 152

—CH₂NHSO₂CH₃ 146 153 —H —CO(CH₂)₄Br —CH₂NHSO₂CH₃ 147 154

—CH₂NHSO₂CH₃ 148 155 —H —CO(CH₂)₅Br —CH₂NHSO₂CH₃ 149 156

—CH₂NHSO₂CH₃

TABLE 2 (IA-ii)

Ex- am- Com- ple pound No. No. R^(1A) R^(2A) R^(3A) 10 12 —CH₂Ph —CH₂Ph —COCH₃ 10 13 —CH₂Ph —COCH₃ —COCH₃ 12 15 —CH₃ —H —COCH₃ 13 16 —CH₃ —CH₃ —COCH₃ 14 17 —CH₃ —H —COCH₂CH₃ 15 18 —CH₃ —COCH₃ —COCH₂CH₃ 16 19 —CH₃ —COCH₂CH₃ —COCH₂CH₃ 17 20 —CH₃ —CO(CH₂)₂CH₃ —CO(CH₂)₂CH₃ 18 21 —CH₃ —COCH(CH₃)₂ —COCH(CH₃)₂ 76 79 —CH₂CH═CH₂ —COCH₃ —COCH₃ 77 80 —CH₂CH═CH₂ —H —COCH(CH₃)₂ 77 81 —CH₂CH═CH₂ —COCH₃ —COCH(CH₃)₂ 78 82 —H —COC(CH₃)₃ —COC(CH₃)₃ 79 83 —CH₃ —H —COCH(CH₃)₂ 79 84 —CH₃ —COCH₃ —COCH(CH₃)₂ 80 85 —H —COCH(CH₃)₂ —COCH(CH₃)₂ 81 86 —H —H —COCH(CH₃)₂ 81 87 —H —COCH₃ —COCH(CH₃)₂ 82 88 —H —COCH(CH₃)₂ —COCH₃ 83 89 —H

—COCH₃ 84 90 —H —H —COCH₂CH(CH₃)₂ 84 91 —H —COCH(CH₃)₂ —COCH₂CH(CH₃)₂ 85 92 —H —COCH₃ —COC(CH₃)₃ 86 93 —H —COC(CH₃)₃ —COCH₃ *Ph: phenyl

TABLE 3 (IA-iii)

Example Compound No. No. R^(1A) R^(4A) R^(5A) 22 25 —H —CH₃ —CH═CHPh 23 26 —H —(CH₂)₃CH₃ —(CH₂)₃CH₃ 24 27 —H

25 28 —H

26 29 —H

28 31 —H

29 32 —H —CH₃

30 33 —H —CH₃

31 34 —H —CH₃

32 35 —H —CH₃

33 36 —H —CH₃

34 37 —H —CH₃

35 38 —H —CH₃

38 41 —CH₂CH₃ —CH₃

39 42 —H —CH₃

40 43 —H —CH₃

41 44 —H —CH₃

42 45 —H —CH₃

125 132 —H —CH₃

126 133 —H —CH₃

127 134 —H —CH₃

* Ph: phenyl

TABLE 4 (IA-iv)

Y^(1A) Example Compound (Substituting No. No. R^(1A) R^(4A) position) 43 46 —H —CH₃ —CH₃ (2) 44 47 —H —CH₃ —CH₃ (3) 45 48 —H —CH₃ —CH₃ (4) 46 49 —H —CH₂CH₃ —CH₂CH₃ (2) 47 50 —H —CH₃ —OCH₃ (2) 48 51 —H —CH₃ —OCH₃ (3) 50 53 —H —CH₃ —F (2) 51 54 —H —CH₃ —F (3) 52 55 —H —CH₃ —F (4) 53 56 —H —CH₃ —Cl (2) 54 57 —CH₂CH₃ —CH₃ —Cl (2) 55 58 —H —CH₃ —Cl (3) 56 59 —H —CH₃ —Cl (4) 57 60 —H —CH₃ —Br (2) 58 61 —H —CH₃ —OCOCH₃ (2) 60 63 —H —H —OCOCH₃ (3) 61 64 —H —CH₃ —OCOCH₃ (4) 62 65 —H —CH₃ —NO₂ (2) 65 68 —H —CH₃ —OH (2) 66 69 —H —CH₃ —OH (3) 67 70 —H —CH₃ —OH (4) 68 71 —H —CH₃ —CN (3) 69 72 —H —CH₃ —CN (4) 70 73 —H —CH₃ —CF₃ (3) 71 74 —H —CH₃ —COOH (2) 118 125 —CH₂CH₃ —CH₃ —OCOCH₃ (3) 119 126 —CH₂CH₃ —CH₃ —OH (3) 120 127 —H —CH₃ —OCONHCH₂CH₃ (3)

TABLE 5 (IA-v)

Y^(1A) Y^(2A) Example Compound (Substituting (Substituting No. No. position) position) 72 75 —OCH₃ (2) —OCH₃ (6) 73 76 —OH (3) —OH (5) 74 77 —OH (3) —OH (4) 75 78 —CH₃ (2) —CH₃ (4)

TABLE 6 (IA-vi)

Example Compound No. No. R^(1A) R^(4A) R^(5A) 87 94 —H —CH₂CH₃ —Ph 88 95 —H —CH₂NHSO₂CH₃ —Ph 89 96 —CH₃ —CH₂NHSO₂CH₃ —Ph 90 97 —H —CH₂NHSO₂CH₂CH₃ —Ph 91 98 —H —CH₂OCH₃ —Ph 92 99 —H —(CH₂)₂NHSO₂CH₃ —Ph 94 101 —H —CH₂NHCOCF₃ —Ph 97 104 —H —(CH₂)₂N(CH₃)₂ —Ph 98 105 —H —(CH₂)₂COOCH₃ —Ph 99 106 —H —(CH₂)₂COOH —Ph 100 107 —H —(CH₂)₂CONH₂ —Ph 101 108 —H —(CH₂)₂CONHOH —Ph 102 109 —H —(CH₂)₂CONHCH₃ —Ph 103 110 —H —(CH₂)₂CON(CH₃)₂ —Ph 104 111 —H —(CH₂)₂CONH(CH₂)₂OH —Ph 105 112 —H —(CH₂)₂CONH(CH₂)₃CH₃ —Ph 106 113 —H

—Ph 107 114 —H —(CH₂)₃COOCH₃ —Ph 108 115 —H —(CH₂)₃COOH —Ph 109 116 —H —(CH₂)₃CONHCH₃ —Ph 110 117 —H —(CH₂)₃CONH₂ —Ph 123 130 —H —CH₃

128 135 —H —CH₃

154 161 —H

—Ph 155 162 —H

—Ph 156 163 —H

—Ph 156 164 —H

—Ph 157 165 —H

—Ph 158 166 —H —(CH₂)₃OH —Ph 159 167 —H —(CH₂)₃OSO₂NH₂ —Ph * Ph: phenyl * Ph: phenyl, Compound 164: an isomer of Compound 163

TABLE 7 (IA-vii)

Example Compound No. No. R^(1A) R^(4A) R^(5A) 93 100 —H —(CH₂)₂NHSO₂CH₃ —Ph 95 102 —COCH(CH₃)₂ —CH₂NHSO₂CH₃ —Ph 96 103 —H —CH₂NHSO₂CH₃ —Ph 121 128 —H —CH₃

122 129 —H —CH₃

124 131 —H —CH₃

* Ph: phenyl

TABLE 8 (IA-viii)

Example Compound No. No. R^(2A) R^(3A) R^(4A) 111 118 —H —COCH₃ —CH₂NHSO₂CH₃ 112 119 —COC(CH₃)₃ —COCH₃ —CH₂NHSO₂CH₃ 113 120 —H —COC(CH₃)₃ —CH₂NHSO₂CH₃ 114 121 —CO(CH₂)₅Br —COC(CH₃)₃ —CH₂NHSO₂CH₃ 115 122 —CO(CH₂)₅N₃ —COC(CH₃)₃ —CH₂NHSO₂CH₃ 116 123 —CO(CH₂)₅NH₂ —COC(CH₃)₃ —CH₂NHSO₂CH₃ 117 124 —CO(CH₂)₅NHCOCH₃ —COC(CH₃)₃ —CH₂NHSO₂CH₃ 150 157 —H —COC(CH₃)₃ —(CH₂)₂NHSO₂CH₃ 151 158 —CO(CH₂)₃Br —COC(CH₃)₃ —(CH₂)₂NHSO₂CH₃ 153 160 —COC(CH₃)₃ —CSCH₃ —CH₂NHSO₂CH₃ 160 168 —COC(CH₃)₃ —COCH₃ —CH₂NHSO₂CH₂Cl 160 169 —COCH₃ —COCH₃ —CH₂NHSO₂CH₂Cl 161 170 —COC(CH₃)₃ —COCH₃ —CH₂NHSO₂CH═CH₂ 161 171 —COC(CH₃)₃ —COC(CH₃)₃ —CH₂NHSO₂CH═CH₂ 162 172 —COC(CH₃)₃ —COCH₃

163 173 —COC(CH₃)₃ —COCH₃ —CH₂NHSO₂(CH₂)₂NHCH₂CH₃ 164 174 —COC(CH₃)₃ —COCH₃ —CH₂NHSO₂(CH₂)₂N(CH₃)₂ 165 175 —COC(CH₃)₃ —COCH₃ —CH₂NHSO₂(CH₂)₂NH(CH₂)₂OH 166 176 —COC(CH₃)₃ —COC(CH₃)₃ —CH₂NHSO₂(CH₂)₂NHCH₂CH₃ 167 177 —COC(CH₃)₃ —COC(CH₃)₃ —CH₂NHSO₂(CH₂)₂N(CH₃)₂ 168 178 —H —COCH₃ —(CH₂)₂CO₂CH₃ 169 179 —COC(CH₃)₃ —COCH₃ —(CH₂)₂CO₂CH₃ 170 180 —H —COCH(CH₃)₂ —(CH₂)₂NHSO₂CH₃ 171 181 —COC(CH₃)₃ —COCH(CH₃)₂ —(CH₂)₂NHSO₂CH₃ 174 184

—COCH(CH₃)₂ —(CH₂)₂NHSO₂CH₃ 175 185 —COCH₂CH₃ —COCH₂CH₃ —(CH₂)₂NHSO₂CH₃ 176 186 —H —COCH₂CH₃ —(CH₂)₂NHSO₂CH₃ 177 187 —COC(CH₃)₃ —COCH₂CH₃ —(CH₂)₂NHSO₂CH₃ 180 190 —H —COC(CH₃)₃ —(CH₂)₂COOCH₃ 181 191

—COC(CH₃)₃ —(CH₂)₂COOCH₃

TABLE 9 (IA-xii)

Example Compound No. No. R^(1A) R^(2A) R^(3A) R^(4A) 152 159

—COC(CH₃)₃ —(CH₂)₂NHSO₂CH₃ 172 182

—COCH(CH₃)₂ —(CH₂)₂NHSO₂CH₃ 173 183

—COCH(CH₃)₂ —(CH₂)₂NHSO₂CH₃ 178 188

—COCH₂CH₃ —(CH₂)₂NHSO₂CH₃ 179 189

—COCH₂CH₃ —(CH₂)₂NHSO₂CH₃ 182 192

—COC(CH₃)₃ —(CH₂)₂COOCH₃ 183 193

—COC(CH₃)₃ —(CH₂)₂COOH 184 194

—COC(CH₃)₃ —(CH₂)₂CONH(CH₂)₂OH

TABLE 10 (IA-xiii)

Example Compound No. No. R^(2A) R²⁸ Y^(3A) 185 195 —COC(CH₃)₃ —OCOCH₃ —H 186 196 —COC(CH₃)₃ —OH —H 187 197 —H —H —OCOCH₃ 188 198 —COC(CH₃)₃ —H —OCOCH₃ 189 199 —COC(CH₃)₃ —H —OH

TABLE 11 (I-ix)

Example Compound No. No. R² R⁴ 1 1 —COCH₃ —CH₃ 3 3 —COCH₃ —(CH₂)₃CH₃ 6 6 —COCH₃ —Ph 11 14 —H —CH₃ * Ph: phenyl

TABLE 12 (I-x)

Example Compound No. No. R¹ R⁴ R⁵ 19 22 —H —CH₃ —CH₃ 20 23 —H —CH₃ —(CH₂)₃CH₃ 21 24 —H —CH₃ —(CH₂)₂Ph 27 30 —H

36 39 —H —CH₃

37 40 —H —CH₃

* Ph: phenyl

TABLE 13 (I-xi)

Y¹ Example Compound (Substituting No. No. R¹ R⁴ position) 49 52 —H —CH₃ —OCH₃ (4) 59 62 —H —CH₃ —OCOCH₃ (3) 63 66 —H —CH₃ —NO₂ (3) 64 67 —H —CH₃ —NO₂ (4)

Next, the pharmacological activity of typical Compounds (I) will be explained by the following test example.

Test Example 1 Antiproliferative Activity in HCT 116 Human Colon Cancer Cells

HCT 116 cells (ATCC No.: CCL-247) were placed on a 96-well microliter plate (Nunc, 167008) at a density of 1×10³ cells/well. The plate was incubated in a 5% CO₂ incubator at 37° C. for 24 hours, and then to the plate was added test compounds diluted stepwise to 100 mL/well in total, and the plate was further incubated in a 5% CO₂ incubator at 37° C. for 72 hours. To the culture medium, the XTT (sodium 3′-[1-(phenylaminocarbonyl)-3,4-tetrazolium)-bis(4-methoxy-6-nitro)benzenesulfonic acid hydrate) labeling mixture (Roche Diagnostics, 1465015) was dispensed in 50 mL/well portions, then the plate was incubated in a 5% CO₂ incubator at 37° C. for 1 hour, and the absorbance was measured at 490 nm and 655 nm with a microplate spectrophotometer (Bio-Rad, Model 550). The inhibitory activity against cell proliferation was shown as a concentration of 50% proliferation inhibition, GI₅₀.

GI₅₀ calculation method: The value (difference in absorbance) was calculated by subtracting the absorbance at 655 nm from the absorbance at 490 nm of each well. The difference in absorbance obtained from the cells untreated with a test compound was defined as 100%, and compared with the difference in absorbance obtained from the cells treated with the solution of the compound in the known concentration, and thereby the concentration of the compound of 50% inhibition against cell proliferation was calculated to obtain GI₅₀.

The results of the typical compounds obtained in Test example 1 are shown in Table 14. Compounds 138, 152, 165, 170, 173, and 199 showed the GI₅₀ value less than 10 μmol/L.

TABLE 14 Compound No. GI₅₀ (μmol/L) 1 1.0 7 0.48 18 0.62 41 0.60 46 0.57 57 0.53 69 0.23 82 0.18 99 0.063 104 0.074 107 0.061 134 0.40

Compound (I) or Compound (IA), or a pharmacologically acceptable salt thereof, per se, can be administered, however, is generally desired to be provided as a form of various pharmaceutical preparations. Also, the pharmaceutical preparations are used for animals or human.

The pharmaceutical preparations according to the present invention can comprise as an active ingredient Compound (I) or Compound (IA), or a pharmacologically acceptable salt thereof, solely or as a mixture with any other effective ingredient for the treatment. The pharmaceutical preparations are manufactured by mixing the active ingredient with one or more of pharmacologically acceptable carriers using any method well known in the technical field of pharmaceutical science.

As for administration routes, it is preferred to chose the most effective route for the treatment such as oral administration or parenteral administration, for example, intravenous administration and the like.

Examples of formulations for administration include tablets, injections and the like.

Examples of the pharmaceutical carrier used include lactose, mannitol, glucose, hydroxypropyl cellulose, starch, magnesium stearate, sorbitan fatty acid ester, glyceric acid ester, polyvinyl alcohol, distilled water for injection, physiological saline, propylene glycol, polyethylene glycol, ethanol and the like. The pharmaceutical preparation according to the present invention may comprise other various additives such as excipients, lubricants, binders, disintegrator, isotonicities and emulsifiers.

Compound (I) or Compound (IA), or a pharmacologically acceptable salt thereof is generally administered systemically or locally in the form of an oral or parenteral preparation when used for the aforementioned purpose. The dose and the frequency of administration may vary depending on the administration form, the age and body weight of a patient, nature and severity of the condition to be treated, and the like. Generally, 0.1 to 1,000 mg/kg, preferably 0.5 to 500 mg/kg per single administration for an adult may be administered orally or parenterally, once a day or a few times a day, or may be continuously administered intravenously for 1 to 24 hours a day. However, the dose and the frequency of administration may vary depending on the aforementioned various conditions and the like.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be explained in detail with reference to the following examples.

The spectra of proton nuclear magnetic resonance (¹H NMR) used in Examples were measured at 270 or 300 MHz, and exchangeable hydrogen may not always be clearly observed depending on the compound and the measurement conditions. For the descriptions of the multiplicity of signals, those generally applied are used, and the symbol “br” represents an apparent broad signal.

Example 1 (Compound 1)

-   Step 1: Acetophenone (4.00 g, 33.3 mmol) and thiosemicarbazide (3.15     g, 34.6 mmol) were dissolved in methanol (30 mL). To the solution     was added hydrochloric acid (0.1 mL) and the mixture was vigorously     stirred at room temperature for 15 hours. To the reaction mixture     was added water (30 mL), and the deposited crystals were collected     by filtration. The collected crystals were washed with water and     diisopropyl ether, and then dried to obtain     acetophenone=thiosemicarbazone (5.64 g, 88%).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.30 (s, 3H), 7.37-7.40 (m, 3H), 7.91-7.94 (m, 3H), 8.27 (br s, 1H), 10.21 (br s, 1H).

-   Step 2: Acetophenone=thiosemicarbazone (300 mg, 0.889 mmol) obtained     above was dissolved in acetic anhydride (1.0 mL, 11 mmol). After     being refluxing under heating, the solution was cooled to room     temperature with vigorous stirring. To the reaction mixture was     added diisopropyl ether (3 mL), and the deposited crystals were     collected by filtration. After the collected crystals were suspended     in diisopropyl ether and stirred for 3 hours, the crystals were     collected by filtration and dried to obtain Compound 1 (195 mg,     72%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.01 (s, 3H), 2.19 (s, 3H), 2.28 (s, 3H), 7.24-7.36 (br s, 5H), 11.63 (br s, 1H)

Example 2 (Compound 2)

-   Step 1: In a manner similar to that in Step 1 of Example 1,     propiophenone=thiosemicarbazone (759 mg, 88%) was obtained from     propiophenone (541 mg, 3.92 mmol) and thiosemicarbazide (382 mg,     4.18 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 1.01 (t, J=7.4 Hz, 3H), 2.85 (br q, J=7.4 Hz, 2H), 7.39 (m, 3H), 7.89 (m, 3H), 8.24 (br s, 1H), 10.30 (br s, 1H)

-   Step 2: In a manner similar to that in Step 2 of Example 1, Compound     2 (601 mg, 76%) was obtained from propiophenone=thiosemicarbazone     (559 mg, 2.70 mmol) obtained above.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 1.02 (t, J=7.1 Hz, 3H), 2.00 (s, 3H), 2.21 (s, 3H), 2.38 (dt, J=7.1, 7.3 Hz, 1H), 2.85 (dt, J=7.1, 7.3 Hz, 1H), 7.23-7.38 (m, 5H), 11.59 (br s, 1H)

Example 3 (Compound 3)

-   Step 1: In a manner similar to that in Step 1 of Example 1,     n-butyl(phenyl)methanone=thiosemicarbazone (589 mg, 63%) was     obtained from n-butyl(phenyl)methanone (649 mg, 4.00 mmol) and     thiosemicarbazide (367 mg, 4.03 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 0.99 (t, J=7.3 Hz, 3H), 1.38-1.49 (m, 4H), 2.96-2.99 (m, 2H), 7.37-7.39 (m, 3H), 7.87-7.91 (m, 3H), 8.26 (br s, 1H), 10.36 (br s, 1H)

-   Step 2: In a manner similar to that in Step 2 of Example 1, Compound     3 (168 mg, 62%) was obtained from     n-butyl(phenyl)methanone=thiosemicarbazone (200 mg, 0.850 mmol)     obtained above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 0.96 (t, J=7.3 Hz, 3H), 1.25-1.34 (m, 1H), 1.36-1.54 (m, 2H), 1.68-1.80 (m, 1H), 2.18 (s, 3H), 2.20-2.26 (m, 1H), 2.26 (s, 3H), 2.99-3.10 (m, 1H), 7.22-7.40 (m, 5H), 8.22 (br s, 1H)

Example 4 (Compound 4)

-   Step 1: In a manner similar to that in Step 1 of Example 1,     isopropyl(phenyl)methanone=thiosemicarbazone (613 mg, 68%) was     obtained from isopropyl(phenyl)methanone (608 mg, 4.10 mmol) and     thiosemicarbazide (364 mg, 3.99 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 1.07 (d, J=6.9 Hz, 6H), 2.82 (m, 1H), 7.28 (br d, J=6.3 Hz, 2H), 7.51-7.60 (m, 3H), 7.78 (br s, 1H), 8.23 (br s, 1H), 8.43 (br s, 1H)

-   Step 2: In a manner similar to that in Step 2 of Example 1, Compound     4 (217 mg, 52%) was obtained from     isopropyl(phenyl)methanone=thiosemicarbazone (300 mg, 1.36 mmol)     obtained above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.04 (d, J=6.9 Hz, 3H), 1.13 (d, J=6.9 Hz, 3H), 2.09 (s, 3H), 2.19 (s, 3H), 3.86 (m, 1H), 7.25-7.36 (m, 3H), 7.75 (br d, J=7.3 Hz, 2H), 8.08 (br s, 1H)

Example 5 (Compound 5)

In a manner similar to that in Step 1 and 2 of Example 1, Compound 5 (130 mg, 10%) was obtained from cyclopropyl(phenyl)methanone (649 mg, 4.00 mmol) and thiosemicarbazide (367 mg, 4.03 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 0.60-0.98 (m, 4H), 1.84 (s, 3H), 2.34 (s, 3H), 2.45 (m, 1H), 7.20-7.35 (m, 3H), 7.54 (br d, J=8.7 Hz, 2H), 9.40 (br s, 1H)

Example 6 (Compound 6)

In a manner similar to that in Step 1 and 2 of Example 1, Compound 6 (150 mg, 29%) was obtained from benzophenone (0.20 g, 2.19 mmol) and thiosemicarbazide (400 mg, 2.20 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.89 (s, 3H), 2.32 (s, 3H), 7.25-7.52 (m, 10H), 9.13 (br s, 1H)

Example 7 (Compound 7)

-   Step 1: In a manner similar to that in Step 1 of Example 1,     acetophenone=4-methylthiosemicarbazone (1.51 g, 77%) was obtained     from 4-methylthiosemicarbazide (1.00 g, 9.51 mmol) and acetophenone     (1.33 mL, 11.4 mmol). -   Step 2: In a manner similar to that in Step 2 of Example 1, Compound     7 (1.03 g, 47%) was obtained from     acetophenone=4-methylthiosemicarbazone (1.00 g, 9.51 mmol) obtained     above.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.21 (s, 3H), 2.23 (s, 3H), 2.26 (s, 3H), 3.41(s, 3H), 7.28-7.36 (m, 5H)

Example 8 (Compounds 8 and 9)

To a solution of 60% sodium hydride (110 mg, 2.70 mmol) in N,N-dimethylformamide (10.0 mL) was added Compound 1 (50.0 mg, 1.80 mmol) prepared in Example 1, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added ethyl iodide (0.22 mL, 2.70 mmol) and the reaction mixture was further stirred at room temperature for 12 hours. To the reaction mixture was added 5% aqueous ammonium chloride and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/1) to obtain Compound 8 (120 mg, 22%) and Compound 9 (330 mg, 60%).

Compound 8

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.19 (t, J=7.0 Hz, 6H), 2.23 (s, 3H), 2.41 (s, 3H), 3.26 (q, J=7.0 Hz, 4H), 7.21-7.45 (m, 5H)

Compound 9

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.36 (t, J=7.2 Hz , 3H), 2.24 (s, 6H), 2.37 (s, 3H), 3.91 (q, J=7.2 Hz, 2H), 7.22-7.41 (m, 5H)

Example 9 (Compounds 10 and 11)

In a manner similar to that in Example 8, Compound 10 (0.15 g, 26%) and compound 11 (0.27 g, 48%) were obtained from Compound 1 (0.50 g, 1.80 mmol) prepared in Example 1 and n-propyl iodide (0.26 mL, 2.70 mmol).

Compound 10

¹H NMR (270 MHz, CDCl₃) δ (ppm): 0.89 (t, J=7.6 Hz, 6H), 1.61 (br q, J=7.6 Hz, 4H), 2.27 (s, 3H), 2.40 (s, 3H), 3.14 (br t, J=1.3 Hz, 4H), 7.21-7.47 (m, 5H)

Compound 11

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.00 (t, J=7.3 Hz, 3H), 1.74-1.82 (m, 2H), 2.28 (s, 6H), 2.36 (s, 3H), 3.75-3.86 (m, 2H), 7.21-7.44 (m, 5H)

Example 10 (Compounds 12 and 13)

In a manner similar to that in Example 8, Compound 12 (120 mg, 16%) and Compound 13 (0.22 g, 33%) were obtained from Compound 1 (500 mg, 1.80 mmol) prepared in Example 1 and benzyl bromide (0.32 mL, 2.70 mmol).

Compound 12

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.24 (s, 3H), 2.46 (s, 3H), 4.43 (s, 4H), 7.14-7.49 (m, 15H)

Compound 13

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.16 (s, 3H), 2.26 (s, 3H), 2.36 (s, 3H), 5.11 (br s, 2H), 7.22-7.38 (m, 10H)

Example 11 (Compound 14)

To acetophenone=thiosemicarbazone (10.0 g, 51.8 mmol) prepared in Step 1 of Example 1 was added acetic anhydride (4.90 mL, 51.9 mmol) and pyridine (8.40 mL, 104 mmol), and the mixture was stirred at room temperature for 12 hours. After the reaction mixture was concentrated under reduced pressure, ethyl acetate and 2 mol/L aqueous sodium hydroxide was added, and the mixture was subjected to separation. The organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/1) to obtain Compound 14 (9.22 g, 76%).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.12 (s, 3H), 2.31 (s, 3H), 6.49 (br s, 2H), 7.21-7.41 (m, 5H)

Example 12 (Compound 15)

Compound 7 (550 mg, 1.89 mmol) prepared in Example 7 was dissolved in N,N-dimethylformamide (10.0 mL). To the solution was added 60% sodium hydride (0.23 g, 5.75 mmol) and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/1) to obtain Compound 15 (0.31 g, 66%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.17 (s, 3H), 2.41 (s, 3H), 2.91 (br d, J=5.0 Hz, 3H), 3.92 (br s, 1H), 7.25-7.47 (m, 5H)

Example 13 (Compound 16)

To a solution of 60% sodium hydride (50.0 mg, 1.20 mmol) in N,N-dimethylformamide (2.0 mL) was added Compound 14 (100 mg, 0.41 mmol) prepared in Example 11, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added methyl iodide (0.08 mL, 1.24 mmol), and the mixture was further stirred at room temperature for 12 hours. To the reaction mixture was added 5% aqueous ammonium chloride and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/1) to obtain Compound 16 (70.0 mg, 67%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.26 (s, 3H), 2.41 (s, 3H), 2.91 (s, 6H), 7.23-7.48 (m, 5H)

Example 14 (Compound 17)

In a manner similar to that in Example 12, Compound 17 (580 mg, 71%) was obtained from Compound 19 (1.00 g, 3.13 mmol) obtained in the after-mentioned Example 16.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.13 (t, J=7.2 Hz, 3H), 2.39 (s, 3H), 2.61 (q, J=7.2 Hz, 2H), 2.88 (d, J=6.3 Hz, 3H), 4.02 (br d, J=6.3 Hz, 1H), 7.22-7.38 (m, 5H)

Example 15 (Compound 18)

Compound 17 (100 mg, 0.38 mmol) prepared in Example 14 was dissolved in acetone (2.0 mL). To the solution was added acetyl chloride (0.15 mL, 2.11 mmol) and pyridine (0.15 mL, 1.85 mmol), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added ethyl acetate and 2 mol/L aqueous sodium hydroxide, and the solution was subjected to separation. The organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=½) to obtain Compound 18 (0.07 g, 59%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.12 (t, J=7.6 Hz, 3H), 2.27 (s, 3H), 2.35 (s, 3H), 2.65 (q, J=7.6 Hz, 2H), 3.45 (s, 3H), 7.23-7.42 (m, 5H)

Example 16 (Compound 19)

To acetophenone=4-methylthiosemicarbazone (2.00 g, 9.66 mmol) prepared in Step 1 of Example 7 was added propionic anhydride (8.67 mL, 67.6 mmol), and the mixture was heated and stirred at 100° C. for 3 hours. To the reaction mixture was added ethyl acetate and 2 mol/L aqueous sodium hydroxide. After the mixture was stirred at room temperature for 30 minutes, the mixture was subjected to separation. The organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=½) to obtain Compound 19 (1.39 g, 45%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.12 (t, J=7.3 Hz, 3H), 1.17 (t, J=7.5 Hz, 3H), 2.36 (s, 3H), 2.54 (q, J=7.3 Hz, 2H), 2.66 (q, J=7.5 Hz, 2H), 3.45 (s, 3H), 7.21-7.42 (m, 5H)

Example 17 (Compound 20)

In a manner similar to that in Example 16, Compound 20 (1.55 g, 46%) was obtained from acetophenone=4-methylthiosemicarbazone (2.00 g, 9.66 mmol) prepared in Step 1 of Example 7 and butyric anhydride (11.1 mL, 67.8 mmol).

¹H NMR (270 MHz, CDCl₃) d(ppm): 0.95 (t, J=7.3 Hz, 3H), 0.98 (t, J=7.4 Hz, 3H), 1.15-1.78 (m, 4H), 2.35 (s, 3H), 2.49 (t, J=7.3 Hz, 2H), 2.61 (t, J=7.4 Hz, 2H), 3.45 (s, 3H), 7.21-7.42 (m, 5H)

Example 18 (Compound 21)

In a manner similar to that in Example 16, Compound 21 (1.43 g, 43%) was obtained from acetophenone=4-methylthiosemicarbazone (2.00 g, 9.66 mmol) prepared in Step 1 of Example 7 and isobutyric anhydride (11.2 mL, 67.5 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.05-1.25 (m, 12H), 2.34 (s, 3H), 2.99 (q, J=7.3 Hz, 1H), 3.25 (q, J=7.5 Hz, 1H), 3.50 (s, 3H), 7.21-7.45 (m, 5H)

Example 19 (Compound 22)

Step 1: In a manner similar to that in Step 1 of Example 1, acetone=thiosemicarbazone (215 mg, 41%) was obtained from acetone (4.8 g, 40 mmol) and thiosemicarbazide (364 mg, 3.99 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 1.89 (s, 3H), 1.91 (s, 3H), 7.51 (br s, 1H), 7.98 (br s, 1H), 9.90 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 22 (151 mg, 61%) was obtained from acetone=thiosemicarbazone (150 mg, 1.14 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.98 (s, 6H), 2.19 (s, 3H), 2.20 (s, 3H), 9.06 (br s, 1H)

Example 20 (Compound 23)

Step 1: In a manner similar to that in Step 1 of Example 1, 2-hexanone=thiosemicarbazone (671 mg, 97%) was obtained from 2-hexanone (401 mg, 4.00 mmol) and thiosemicarbazide (364 mg, 3.99 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 0.88 (t, J=6.9 Hz, 3H), 1.23-1.31 (m, 2H), 1.41-1.50 (m, 2H), 1.88 (s, 3H), 2.17-2.23 (m, 2H), 7.44 (br s, 1H), 8.02 (br s, 1H), 9.88 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 23 (255 mg, 57%) was obtained from 2-heranone=thiosemicarbazone (300 mg, 1.73 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 0.90 (t, J=6.9 Hz, 3H), 1.23-1.38 (m, 3H), 1.52-1.56 (m, 1H), 1.84-2.18 (m, 1H), 1.97 (s, 3H), 2.18 (s, 3H), 2.19 (s, 3H), 2.44-2.55 (m, 1H), 8.68 (br s, 1H)

Example 21 (Compound 24)

Step 1: In a manner similar to that in Step 1 of Example 1, benzylacetone=thiosemicarbazone (788 mg, 89%) was obtained from benzylacetone (593 mg, 4.00 mmol) and thiosemicarbazide (367 mg, 4.03 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 1.92 (s, 3H), 2.52 (m, 2H), 2.84 (m, 2H), 7.14-7.30 (m, 5H), 7.43 (br s, 1H), 8.03 (br s, 1H), 9.94 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 24 (382 mg, 92%) was obtained from benzylacetone=thiosemicarbazone (300 mg, 1.36 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.00 (s, 3H), 2.17 (s, 3H), 2.13 (dd, J=2.3, 10.2 Hz, 1H), 2.19 (s, 3H), 2.59 (dd, J=2.2, 10.2 Hz, 1H), 2.87 (br d, J=12.2 Hz, 1H), 2.95 (br s, J=11.8 Hz, 1H), 7.14-7.29 (m, 5H), 8.39 (br s, 1H)

Example 22 (Compound 25)

Step 1: In a manner similar to that in Step 1 of Example 1, benzylideneacetone=thiosemicarbazone (730 mg, 80%) was obtained 1 from benzylideneacetone (610 mg, 4.17 mmol) and thiosemicarbazide (371 mg, 4.07 mmol).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 2.13 (s, 3H), 6.89 (d, J=16.8 Hz, 1H), 7.10 (d, J=16.8 Hz, 1H), 7.27-7.41 (m, 3H), 7.43-7.56 (m, 2H), 7.78 (br s, 1H), 8.26 (br s, 1H), 10.27 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 25 (195 mg, 72%) was obtained from benzylideneacetone=thiosemicarba.zone (300 mg, 0.889 mmol) prepared above.

¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 2.13 (s, 3H), 2.15 (s, 3H), 2.23 (s, 3H), 6.62 (d, J=12.2 Hz, 1H), 6.65 (d, J=12.2 Hz, 1H), 7.20-7.39 (m, 5H), 8.57 (br s, 1H)

Example 23 (Compound 26)

Step 1: In a manner similar to that in Step 1 of Example 1, 5-Nonanone=thiosemicarbazone (553 mg, 64%) was obtained from 5-nonanone (569 mg, 4.00 mmol) and thiosemicarbazide (364 mg, 3.99 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 0.87 (t, J=6.9 Hz, 6H), 1.20-1.53 (m, 8H), 2.17-2.22 (m, 2H), 2.31-2.37 (m, 2H), 7.40 (br s, 1H), 8.00 (br s, 1H), 10.03 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 26 (245 mg, 59%) was obtained from 5-nonanone=thiosemicarbazone (300 mg, 1.39 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 0.90 (t, J=6.9 Hz, 6H), 1.18-1.37 (m, 6H), 1.55-1.63 (m, 2H), 1.77-1.88 (m, 2H), 2.18 (s, 3H), 2.19 (s, 3H), 2.45-2.56 (m, 2H), 8.90 (br s, 1H)

Example 24 (Compound 27)

Step 1: In a manner similar to that in Step 1 of Example 1, a-tetralone=thiosemicarbazone (797 mg, 88%) was obtained from a-tetralone (604 mg, 4.13 mmol) and thiosemicarbazide (368 mg, 4.04 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 1.78-1.82 (m, 2H), 2.65-2.75 (m, 4H), 7.15-7.27 (m, 3H), 7.97 (br s, 1H), 8.20-8.40 (m, 2H), 10.10 (br a, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 27 (324 mg, 78%) was obtained from a-tetralone=thiosemicarbazone (300 mg, 1.37 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.89 (s, 3H), 2.09-2.22 (m, 2H), 2.28 (s, 3H), 2.36-2.41 (m, 1H), 2.80-2.86 (m, 2H), 2.97-3.08 (m, 1H), 7.01 (br d, J=8.6 Hz, 1H), 7.08-7.18 (m, 2H), 7.40 (br d, J=7.3 Hz, 1H), 9.24 (br s, 1H)

Example 25 (Compound 28)

Step 1: In a manner similar to that in Step 1 of Example 1, β-tetralone=thiosemicarbazone (684 mg, 75%) was obtained from 8-tetralone (607 mg, 4.15 mmol) and thiosemicarbazide (379 mg, 4.16 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 28 (301 mg, 65%) was obtained from β-tetralone=thiosemicarbazone (334 mg, 1.53 mmol) prepared above.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.12 (s, 3H), 2.15-2.30 (m, 1H), 2.24 (s, 3H), 3.05-3.09 (m, 2H), 3.14 (br d, J=15.8 Hz, 1H), 3.23-3.41 (m, 1H), 4.38 (br d, J=15.8 Hz, 1H), 6.99-7.00 (m, 1H), 7.02-7.25 (m, 3H), 8.42 (br s, 1H)

Example 26 (Compound 29)

Step 1: In a manner similar to that in Step 1 of Example 1, 1-indanone=thiosemicarbazone (1.54 g, 94%) was obtained from 1-indanone (1.06 g, 8.00 mmol) and thiosemicarbazide (740 mg, 8.12 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.85-2.89 (m, 2H), 3.03-3.08 (n, 2H), 7.28-7.38 (m, 3H), 7.87 (br d, J=7.6 Hz, 1H), 7.92 (br s, 1H), 8.17 (br s, 1H), 10.2 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 29 (184 mg, 44%) was obtained from 1-indanone=thiosemicarbazone (300 mg, 1.46 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.17 (s, 3H), 2.24 (s, 3H), 2.58-2.65 (m, 1H), 2.96-3.07 (m, 1H), 3.13-3.21 (m, 2H), 7.15-7.27 (m, 3H), 7.32-7.37 (m, 1H), 9.60 (br s, 1H)

Example 27 (Compound 30)

Step 1: In a manner similar to that in Step 1 of Example 1, cyclohexanone=thiosemicarbazone (479 mg, 70%) was obtained from cyclohexanone (393 mg, 4.00 mmol) and thiosemicarbazide (364 mg, 3.99 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 1.55 (br s, 6H), 2.19-2.23 (m, 2H), 2.38 (br s, 2H), 7.50 (br s, 1H), 7.93 (br s, 1H), 10.13 (br s, 1H)

Step 2: In a manner'similar to that in Step 2 of Example 1, Compound 30 (214 mg, 72%) was obtained from cyclohexanone=thiosemicarbazone (200 mg, 1.17 mmol) prepared above.

¹H NMR (300 MHz, CDCl₃) δ (ppm): 1.25-1.53 (n, 3H), 1.58-1.68 (m, 1H), 1.81-1.86 (m, 2H), 2.03-2.08 (m, 2H), 2.16 (s, 3H), 2.17 (s, 3H), 2.90-3.01 (m, 2H), 7.95 (br s, 1H)

Example 28 (Compound 31)

In a manner similar to that in Step 1 and 2 of Example 1, Compound 31 (214 mg, 20%) was obtained from 2-norbornanone (452 mg, 4.10 mmol) and thiosemicarbazide (377 mg, 4.14 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.32-1.67 (m, 5H), 1.76-1.89 (m, 2H), 2.18 (s, 3H), 2.19 (br s, 1H), 2.21 (s, 3H), 2.26 (br s, 1H), 3.60 (br d, J=13.9 Hz, 1H), 8.20 (br s, 1H)

Example 29 (Compound 32)

In a manner similar to that in Step 1 and 2 of Example 1, Compound 32 (214 mg, 32%) was obtained from 1′-acetonaphthone (344 mg, 2.02 mmol) and thiosemicarbazide (190 mg, 2.08 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.06 (s, 3H), 2.07 (s, 3H), 2.33 (s, 3H), 7.45-7.65 (m, 4H), 7.89-7.99 (m, 3H), 11.50 (br s, 1H).

Example 30 (Compound 33)

Step 1: In a manner similar to that in Step 1 of Example 1, 2′-acetonaphthone=thiosemicarbazone (448 mg, 92%) was obtained from 2′-acetonaphthone (342 mg, 2.10 mmol) and thiosemicarbazide (189 mg, 2.07 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.42 (s, 3H), 7.53 (m, 2H), 7.86-8.05 (m, 4H), 8.28-8.34 (m, 3H), 10.28 (br a, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 33 (302 mg, 90%) was obtained from 2′-acetonaphthone=thiosemicarbazone (250 mg, 1.03 mmol) prepared above.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.02 (s, 3H), 2.22 (s, 3H), 2.38 (s, 3H), 7.51-7.55 (m, 3H), 7.85-7.95 (m, 4H), 11.68 (br s, 1H)

Example 31 (Compound 34)

Step 1: In a manner similar to that in Step 1 of Example 1, 1-(2-pyridyl)ethanone=thiosemicarbazone (694 mg, 88%) was obtained from 2-acetylpyridine (485 mg, 4.00 mmol) and thiosemicarbazide (369 mg, 4.05 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.38 (s, 3H), 7.37 (br t, J=6.3 Hz, 1H), 7.78 (br t, J=7.2 Hz, 1H), 8.13 (br s, 1H), 8.40 (br s, 1H), 8.41 (br d, J=8.2 Hz, 1H), 8.56 (br d, J=6.6 Hz, 1H), 10.31 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 34 (160 mg, 37%) was obtained from 1-(2-pyridypethanone=thiosemicarbazorte (304 mg, 1.56 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.09 (s, 3H), 2.26 (s, 3H), 2.42 (s, 3H), 7.17 (br t, J=6.9 Hz, 1H), 7.38 (br d, J=8.2 Hz, 1H), 7.68 (br t, J=7.7 Hz, 1H), 8.44 (br s, 1H), 8.58 (br d, J=6.3 Hz, 1H)

Example 32 (Compound 35)

Step 1: In a manner similar to that in Step 1 of Example 1, 1-(3-pyridyl)ethanone=thiosemicarbazone (722 mg, 93%) was obtained from 3-acetylpyridine (484 mg, 4.00 mmol) and thiosemicarbazide (388 mg, 4.00 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.32 (s, 3H), 7.32-7.42 (m, 1H), 8.07 (br s, 1H), 8.29-8.34 (m, 2H), 8.54-8.57 (m, 1H), 9.09 (br s, 1H), 10.32 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 35 (213 mg, 72%) was obtained from 1-(3-pyridypethanone=thiosemicarbazone (205 mg, 1.05 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.14 (s, 3H), 2.21 (s, 3H), 2.39 (s, 3H), 7.31 (br dd, J=5.4, 7.9 Hz, 1H), 7.75 (br d, J=7.9 Hz, 1H), 8.52 (br d, J=5.4 Hz, 1H), 8.72 (br s, 1H), 9.08 (br s, 1H)

Example 33 (Compound 36)

Step 1: In a manner similar to that in Step 1 of Example 1, 1-(4-pyridyl)ethanone=thiosemicarbazone (722 mg, 95%) was obtained from 4-acetylpyridine (507 mg, 4.19 mmol) and thiosemicarbazide (408 mg, 4.46 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 36 (389 mg, 85%) was obtained from 1-(4-pyridyl)ethanone=thiosemicarbazone (318 mg, 1.64 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.16 (s, 3H), 2.25 (s, 3H), 2.35 (s, 3H), 7.30 (d, J=6.3 Hz, 2H), 8.46 (br s, 1H), 8.60 (d, J=6.3 Hz, 2H)

Example 34 (Compound 37)

Step 1: In a manner similar to that in Step 1 of Example 1, 1-pyrazinylethanone=thiosemicarbazone (714 mg, 92%) was obtained from acetylpyrazine (489 mg, 4.00 mmol) and thiosemicarbazide (366 mg, 4.00 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 37 (489 mg, 85%) was obtained from 1-pyrazinylethanone=thiosemicarbazone (400 mg, 2.05 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.16 (s, 3H), 2.26 (s, 3H), 2.42 (s, 3H), 8.06 (br s, 1H), 8.46 (d, J=2.7 Hz, 1H), 8.52 (dd, J=1.7, 2.7 Hz, 1H), 8.71 (d, J=1.7 Hz, 1H)

Example 35 (Compound 38)

Step 1: In a manner similar to that in Step 1 of Example 1, 1-(2-pyrrolyl)ethanone=thiosemicarbazone (408 mg, 55%) was obtained from 2-acetylpyrrole (437 mg, 4.00 mmol) and thiosemicarbazide (374 mg, 4.09 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 38 (504 mg, 95%) was obtained from 1-(2-pyrrolyl)ethanone=thiosemicarbazone (314 mg, 1.72 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.12 (s, 3H), 2.21 (s, 3H), 2.38 (s, 3H), 2.55 (s, 3H), 6.17-6.22(m, 2H), 7.11 (br s, 1H), 8.13 (br s, 1H)

Example 36 (Compound 39)

Step 1: In a manner similar to that in Step 1 of Example 1, 1-(2-furyl)ethanone=thiosemicarbazone (441 mg, 60%) was obtained from 2-acetylfuran (444 mg, 4.00 mmol) and thiosemicarbazide (368 mg, 4.03 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 39 (217 mg, 83%) was obtained from 1-(2-furyl)ethanone=thiosemicarbazone (180 mg, 0.982 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.13 (s, 3H), 2.22 (s, 3H), 2.30 (s, 3H), 6.31 (m, 2H), 7.36 (br s, 1H), 8.43 (br s, 1H)

Example 37 (Compound 40)

Step 1: In a manner similar to that in Step 1 of Example 1, 1-(2-thienyl)ethanone=thiosemicarbazone (636 mg, 78%) was obtained from 2-acetylthiophene (521 mg, 4.13 mmol) and thiosemicarbazide (376 mg, 4.11 mmol).

Step 2: In a manner similar to that in Step 2 of. Example 1, Compound 40 (549 mg, 78%) was obtained from 1-(2-thienyl)ethanone=thiosemicarbazone (498 mg, 2.50 mmol) prepared above.

¹H NMR (300 MHz, CDCl₃) δ (ppm): 2.07 (s, 3H), 2.24 (s, 3H), 2.42 (s, 3H), 6.89 (br t, J=7.2 Hz, 1H), 7.06 (dd, J=6.9, 7.2 Hz 1H), 7.24 (br d, J=6.9 Hz, 1H), 8.81 (br s, 1H)

Example 38 (Compound 41)

In a manner similar to that in Example 8, Compound 41 (148 mg, 52%) was obtained in from Compound 40 (260 mg, 0.918 mmol) prepared in Example 37.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.36 (t, J=7.0 Hz, 3H), 2.25 (s, 3H), 2.30 (s, 3H), 2.43 (s, 3H), 3.92 (br q, J=7.0 Hz, 2H), 6.91 (br t, J=5.2 Hz, 1H), 7.06 (br d, J=5.2 Hz, 1H), 7.24 (br d, J=5.2 Hz, 1H)

Example 39 (Compound 42)

Step 1: In a manner similar to that in Step 1 of Example 1, 1-(3-methyl-2-thienyl)ethanone=thiosemicarbazone (410 mg, 48%) was obtained from 2-acetyl-3-methylthiophene (561 mg, 4.00 mmol) and thiosemicarbazide (374 mg, 4.09 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 42 (335 mg, 93%) was obtained from 1-(3-methyl-2-thienyDethanone=thiosemicarbazone (260 mg, 1.22 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.02 (s, 3H), 2.19 (s, 3H), 2.24 (s, 3H), 2.38 (s, 3H), 6.78 (d, J=5.0 Hz, 1H), 7.07 (d, J=5.0 Hz, 1H), 9.37 (br s, 1H)

Example 40 (Compound 43)

Step 1: In a manner similar to that in Step 1 of Example 1, 1-(benzo[b]thiophen-2-yl)ethanone=thiosemicarbazone (990 mg, 99%) was obtained from 1-(benzo[b]thiophen-2-yl)ethanone (705 mg, 4.00 mmol) and thiosemicarbazide (370 mg, 4.05 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.40 (s, 3H), 7.36-7.41 (m, 2H), 7.45 (br s, 1H), 7.81-7.90 (m, 3H), 8.42 (br s, 1H), 10.56 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 43 (599 mg, 90%) was obtained from 1-(benzo[b]thiophen-2-yl)ethanone=thiosemicarbazone (500 mg, 2.01 mmol) prepared above.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.04 (s, 3H), 2.17 (s, 3H), 2.38 (s, 3H), 7.31-7.40 (m, 3H), 7.79 (br d, J=7.6 Hz, 1H), 7.89 (br d, J=7.8 Hz, 1H), 11.75 (br s, 1H)

Example 41 (Compound 44)

Step 1: In a manner similar to that in Step 1 of Example 1, 1-(3-thienyl)ethanone=thiosemicarbazone (839 mg, 98%) was obtained from 3-acetylthiophene (520 mg, 4.12 mmol) and thiosemicarbazide (366 mg, 4.00 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.27 (s, 3H), 7.52 (br d, J=5.3 Hz, 1H), 7.83 (br d, J=5.3 Hz, 1H), 7.95 (br s, 1H), 8.22 (br s, 1H), 10.08 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 44 (540 mg, 83%) was obtained from 1-(3-thienyl)ethanone=thiosemicarbazone (458 mg, 2.30 mmol) prepared above.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.02 (s, 3H), 2.15 (s, 3H), 2.25 (s, 3H), 7.05 (br d, J=6.0 Hz, 1H), 7.37 (br s, 1H), 7.47 (br d, J=6.0 Hz, 1H)

Example 42 (Compound 45)

Step 1: In a manner similar to that in Step 1 of Example 1, 1-(2-thiazolyl)ethanone=thiosemicarbazone (711 mg, 90%) was obtained from 2-acetylthiazole (379 mg, 4.15 mmol) and thiosemicarbazide (366 mg, 4.00 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.42 (s, 3H), 7.67 (br s, 1H), 7.79 (br d, J=4.3 Hz, 1H), 7.87 (br d, J=4.3 Hz, 1H), 8.51 (br s, 1H), 10.65 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 45 (374 mg, 45%) was obtained from 1-(2-thiazolyl)ethanone=thiosemicarbazone (374 mg, 1.87 mmol) prepared above.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.03 (s, 3H), 2.18 (s, 3H), 2.31 (s, 3H), 7.74-7.79 (m, 2H), 11.70 (br s, 1H)

Example 43 (Compound 46)

In a manner similar to that in Step 1 and 2 of Example 1, Compound 46 (141 mg, 10%) was obtained from 2′-methylacetophenone (627 mg, 4.67 mmol) and thiosemicarbazide (374 mg, 4.09 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.99 (br s, 1H), 2.21 (s, 3H), 2.33 (s, 3H), 2.38 (s, 3H), 7.15-7.20 (m, 3H), 7.38 (m, 1H), 8.90 (br s, 1H)

Example 44 (Compound 47)

Step 1: In a manner similar to that in Step 1 of Example 1, 3′-methylacetophenone=thiosemicarbazone (791 mg, 89%) was obtained from 3′-methylacetophenone (540 mg, 4.02 mmol) and thiosemicarbazide (369 mg, 4.04 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 47 (316 mg, 79%) was obtained from 3′-methylacetophenone=thiosemicarbazone (300 mg, 1.36 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.15 (s, 3H), 2.23 (s, 3H), 2.34 (s, 3H), 2.37 (s, 3H), 7.01-7.09 (m, 1H), 7.19-7.30 (m, 3H), 7.90 (br s, 1H)

Example 45 (Compound 48)

Step 1: In a manner similar to that in Step 1 of Example 1, 4′-methylacetophenone=thiosemicarbazone (767 mg, 93%) was obtained from 4′-methylacetophenone (536 mg, 3.99 mmol) and thiosemicarbazide (382 mg, 4.19 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.27 (s, 3H), 2.32 (s, 3H), 7.18 (d, J=7.9 Hz, 2H), 7.82 (d, J=7.9 Hz, 2H), 7.88 (br s, 1H), 8.23 (br s, 1H), 10.15 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 48 (224 mg, 80%) was obtained from 4′-methylacetophenone=thiosemicarbazone (200 mg, 0.965 mmol) prepared above.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.06 (s, 3H), 2.24 (s, 3H), 2.31 (s, 3H), 2.36 (s, 3H), 7.13 (d, J=8.3 Hz, 2H), 7.31 (d, J=8.3 Hz, 2H), 8.40 (br s, 1H)

Example 46 (Compound 49)

Step 1: In a manner similar to that in Step 1 of Example 1, 2′-ethylpropiophenone=thiosemicarbazone (672 mg, 71%) was obtained from 2′-ethylpropiophenone (649 mg, 4.00 mmol) and thiosemicarbazide (378 mg, 4.14 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 49 (759 mg, 88%) was obtained from 2′-ethylpropiophenone=thiosemicarbazone (300 mg, 1.27 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.13 (t, J=6.9 Hz, 3H), 1.24 (t, J=7.3 Hz, 3H), 1.96 (s, 3H), 2.20 (m, 1H), 2.24 (s, 3H), 2.71 (m, 2H), 3.14 (m, 1H), 7.13 (br t, J=7.1 Hz, 1H), 7.21-7.26 (m, 2H), 7.51 (br d, J=7.9 Hz, 1H), 8.87 (br s, 1H)

Example 47 (Compound 50)

Step 1: In a manner similar to that in Step 1 of Example 1, 2′-methoxyacetophenone=thiosemicarbazone (891 mg, 92%) was obtained from 2′-methoxyacetophenone (601 mg, 4.00 mmol) and thiosemicarbazide (366 mg, 4.00 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 50 (64.0 mg, 93%) was obtained from 2′-methoxyacetophenone=thiosemicarbazone (50.0 mg, 0.224 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.08 (s, 3H), 2.29 (s, 3H), 2.45 (s, 3H), 3.87 (s, 3H), 6.90 (br t, J=7.3 Hz, 1H), 6.91 (br d, J=7.3 Hz, 1H), 7.06 (br d, J=7.3 Hz, 1H), 7.27 (br t, J=7.3 Hz, 1H), 8.31 (br s, 1H)

Example 48 (Compound 51)

Step 1: In a manner similar to that in Step 1 of Example 1, 3′-methoxyacetophenone=thiosemicarbazone (713 mg, 58%) was obtained from 3′-methoxyacetophenone (601 mg, 4.00 mmol) and thiosemicarbazide (377 mg, 4.12 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.29 (s, 311), 3.80 (s, 3H), 6.96 (br d, J=7.9 Hz, 1H), 7.30 (br t, J=7.9 Hz, 111), 7A4 (br s, 111), 7.46 (br d, J=7.9 Hz, 1H), 7.94 (br s, 1H), 8.28 (br s, 1H), 10.18 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 51 (419 mg, 71%) was obtained from 3′-methoxyacetophenone=thiosemicarbazone (500 mg, 2.24 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.10 (s, 311), 2.30 (s, 3H), 2.34 (s, 3H), 3.78 (s, 3H), 6.78 (br d, J=7.9 Hz, 1H), 6.94 (br s, 1H), 7.01 (br d, J=7.9 Hz, 1H), 7.25 (br t, J=7.9 Hz, 1H), 9.48 (br s, 1H)

Example 49 Compound 52

Step 1: In a manner similar to that in Step 1 of Example 1, 4′-methoxyacetophenone=thiosemicarbazone (448 mg, 83%) was obtained from 4′-methoxyacetophenone (362 mg, 2.41 mmol) and thiosemicarbazide (225 mg, 2.46 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 52 (248 mg, 90%) was obtained from 4′-methoxyacetophenone=thiosexnicarbazone (200 mg, 0.896 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.06 (s, 3H), 2.24 (a, 3H), 2.35 (s, 3H), 3.78 (s, 3H), 6.84 (d, J=8.6 Hz, 2H), 7.36 (d, J=8.6 Hz, 2H), 8.56 (br s, 1H)

Example 50 Compound 53

Step 1: In a manner similar to that in Step 1 of Example 1, 2′-fluoroacetophenone=thiosemicarbazone (704 mg, 83%) was obtained from 2′-fluoroacetophenone (558 mg, 4.04 mmol) and thiosemicarbazide (385 mg, 4.12 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.29 (s, 3H), 7.19-7.28 (m, 2H), 7.40-7.48 (m, 1H), 7.74-7.80 (m, 2H), 8.30 (br s, 1H), 10.34 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 53 (199 mg, 71%) was obtained from 2′-fluoroacetophenone=thiosemicarbazone (200 mg, 0.948 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.05 (s, 3H), 2.26 (s, 3H), 2.40 (s, 3H), 7.01-7.12 (m, 2H), 7.23-7.31 (m, 2H), 8.68 (br s, 1H)

Example 51 Compound 54

Step 1: In a manner similar to that in Step 1 of Example 1, 3′-fluoroacetophenone=thiosemicarbazone (772 mg, 92%) was obtained from 3′-fluoroacetophenone (553 mg, 4.00 mmol) and thiosemicarbazide (372 mg, 4.07 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.29 (s, 3H), 7.17-7.24 (m, 1H), 7.38-7.46 (m, 1H), 7.69 (br d, J=8.9 Hz, 1H), 7.88 (br d, J=11.2 Hz, 1H), 8.09 (br s, 1H), 8.31 (br s, 1H), 10.24 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 54 (242 mg, 74%) was obtained from 3′-fluoroacetophenone=thiosemicarbazone (233 mg, 1.10 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.08 (s, 3H), 2.26 (s, 3H), 2.35 (s, 3H), 6.92-6.99 (m, 1H), 7.07-7.13 (m, 1H), 7.18-7.22 (m, 1H), 7.28-7.34 (m, 1H), 8.54 (br s, 1H)

Example 52 Compound 55

Step 1: In a manner similar to that in Step 1 of Example 1, 4′-fluoroacetophenone=thiosemicarbazone (769 mg, 91%) was obtained from 4′-fluoroacetophenone (553 mg, 4.00 mmol) and thiosemicarbazide (376 mg, 4.11 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 55 (251 mg, 86%) was obtained from 4′-fluoroacetopbenone=thiosemicarbazone (208 mg, 0.986 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.14 (s, 3H), 2.22 (s, 3H), 2.36 (s, 3H), 6.98-7.05 (m, 2H), 7.38-7.44 (m, 2H), 8.09 (br s, 1H)

Example 53 Compound 56

Step 1: In a manner similar to that in Step 1 of Example 1, 2′-chloroacetophenone=thiosemicarbazone (362 mg, 58%) was obtained from 2′-chloroacetophenone (344 mg, 2.23 mmol) and thiosemicarbazide (194 mg, 2.12 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 56 (347 mg, 97%) was obtained from 2′-chloroacetophenone=thiosemicarbazone (200 mg, 1.14 mmol) prepared above.

¹NMR (270 MHz, CDCl₃) δ (ppm): 1.98 (s, 3H), 2.23 (s, 3H), 2.38 (s, 3H), 7.22-7.27 (m, 2H), 7.37-7.45 (m, 2H), 9.05 (br s, 1H)

Example 54 Compound 57

In a manner similar to that in Example 8, Compound 57 (347 mg, 97%) was obtained from Compound 56 (200 mg, 1.14 mmol) prepared in Example 53.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.35 (t, J=6.9 Hz, 3H), 2.25 (s, 3H), 2.30 (s, 3H), 2.40 (s, 3H), 3.91-3.93 (br s, 2H), 7.22-7.28 (m, 2H), 7.38-7.42 (m, 2H)

Example 55 Compound 58

Step 1: In a manner similar to that in Step 1 of Example 1, 3′-chloroacetophenone=thiosemicarbazone (211 mg, 45%) was obtained from 3′-chloroacetophenone (319 mg, 2.06 mmol) and thiosemicarbazide (188 mg, 2.06 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 58 (347 mg, 97%) was obtained from 3′-chloroacetophenone=thiosemicarbazone (200 mg, 1.14 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.01 (s, 3H), 2.19 (s, 3H), 2.25 (s, 3H), 7.29-7.41 (m, 4H), 11.68 (br s, 1H)

Example 56 Compound 59

Step 1: In a manner similar to that in Step 1 of Example 1, 4′-chloroacetophenone=thiosemicarbazone (362 mg, 58%) was obtained from 4′-chloroacetophenone (344 mg, 2.23 mmol) and thiosemicarbazide (194 mg, 2.06 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 59 (193 mg, 86%) was obtained from 4′-chloroacetophenone=thiosemicarbazone (164 mg, 0.720 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.11 (s, 3H), 2.23 (s, 3H), 2.24 (s, 3H), 7.30 (d, J=8.6 Hz, 2H), 7.36 (d, J=8.6 Hz, 2H), 8.34 (br s, 1H)

Example 57 Compound 60

Step 1: In a manner similar to that in Step 1 of Example 1, 2′-bromoacetophenone=thiosemicarbazone (392 mg, 69%) was obtained from 2′-bromoacetophenone (415 mg, 2.08 mmol) and thiosemicarbazide (190 mg, 2.08 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.28 (s, 3H), 7.29-7.76 (m, 5H), 8.25 (br s, 1H), 10.35 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 60 (328 mg, 99%) was obtained from 2′-bromoacetophenone=thiosemicarbazone (254 mg, 0.933 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.01 (s, 3H), 2.23 (s, 3H), 2.38 (s, 3H), 7.13 (br t, J=7.6 Hz, 1H), 7.30 (br t, J=7.6 Hz, 1H), 7.47 (br d, J=7.6 Hz, 1H), 7.62 (br s, J=7.6 Hz, 1H), 8.86 (br s, 1H)

Example 58 Compound 61

Step 1: In a manner similar to that in Step 1 of Example 1, 2′-hydroxyacetophenone=thiosemicarbazone (649 mg, 78%) was obtained from 2′-hydroxyacetophenone (544 mg, 4.00 mmol) and thiosemicarbazide (377 mg, 4.12 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.31 (s, 3H), 6.85 (br t, J=7.0 Hz, 1H), 6.88 (br d, J=7.0 Hz, 1H), 7.25 (br t, J=7.0 Hz, 1H), 7.50 (br s, 1H), 7.53 (br d, J=7.0 Hz, 1H), 7.81 (br s, 1H), 8.10 (br s, 1H), 10.35 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 61 (322 mg, 70%) was obtained from 2″-hydroxyacetophenone=thiosemicarbazone (233 mg, 1.10 mmol) prepared above.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.04 (s, 3H), 2.06 (s, 3H), 2.23 (s, 3H), 2.24 (s, 3H), 7.12 (br d, J=7.6 Hz, 1H), 7.23 (br t, J=7.6 Hz, 1H), 7.35 (br t, J=7.6 Hz, 1H), 7.39 (br d, J=7.6 Hz, 1H), 10.20 (br s, 1H)

Example 59 Compound 62

Step 1: In a manner similar to that in Step 1 of Example 1, 3′-hydroxyacetophenone=thiosemicarbazone (654 mg, 78%) was obtained from 3′-hydroxyacetophenone (546 mg, 4.01 mmol) and thiosemicarbazide (379 mg, 4.15 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 62 (351 mg, 84%) was obtained from 3′-hydroxyacetophenone=thiosemicarbazone (262 mg, 1.25 mmol) prepared above.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 1.96 (s, 3H), 2.27 (s, 3H), 2.28 (s, 3H), 2.34 (s, 3H), 7.07 (br d, J=8.4 Hz, 1H), 7.15 (br s, 1H), 7.32 (br d, J=8.4 Hz, 1H), 7.33 (br t, J=8.4 Hz, 1H), 9.24 (br s, 1H)

Example 60 Compound 63

Step 1: In a manner similar to that in Step 1 of Example 1, 3′-hydroxybenzaldehyde=thiosemicarbazone (732 mg, 88%) was obtained from 3′-hydroxybenzaldehyde (488 mg, 4.00 mmol) and thiosemicarbazide (378 mg, 4.15 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 6.80 (m, 1H), 7.13 (br s, 1H), 7.19 (m, 2H), 7.87 (br s, 1H), 7.96 (s, 1H), 8.14 (br s, 1H), 9.66 (br s, 1H), 11.35 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 63 (322 mg, 70%) was obtained from 3′-hydroxybenzaldehyde=thiosemicarbazone (300 mg, 1.43 mmol) prepared above.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.18 (s, 3H), 2.25 (s, 3H), 2.28 (s, 3H), 6.86 (s, 1H), 7.04 (br d, J=7.4 Hz, 1H), 7.05 (s, 1H), 7.19 (br d, J=7.4 Hz, 1H), 7.31 (br t, J=7.4 Hz, 1H), 8.16 (br s, 1H)

Example 61 Compound 64

Step 1: In a manner similar to that in Step 1 of Example 1, 4′-hydroxyacetophenone=thiosemicarbazone (830 mg, 99%) was obtained from 4′-hydroxyacetophenone (544 mg, 4.00 mmol) and thiosemicarbazide (387 mg, 425 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.23 (s, 3H), 6.75 (d, J=8.5 Hz, 2H), 7.76 (d, J=8.5 Hz, 2H), 7.78 (br s, 1H), 8.14 (br s, 1H), 9.75 (s, 1H), 10.05 (s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 64 (199 mg, 61%) was obtained from 4′-hydroxyacetophenone=thiosemicarbazone (202 mg, 0.965 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.15 (s, 3H), 2.22 (s, 3H), 2.23 (s, 3H), 2.29 (s, 3H), 7.07 (br d, J=8.6 Hz, 2H), 7.43 (br d, J=8.6 Hz, 2H), 7.99 (br s, 1H)

Example 62 Compound 65

Step 1: In a manner similar to that in Step 1 of Example 1, 2′-nitroacetophenone=thiosemicarbazone (785 mg, 81%) was obtained from 2′-nitroacetophenone (673 mg, 4.08 mmol) and thiosemicarbazide (365 mg, 3.99 mmol).

1H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.27 (s, 3H), 7.32 (br s, 1H), 7.60-7.68 (m, 1H), 7.72-7.79 (m, 2H), 7.96 (br d, J=7.9 Hz, 1H), 8.31 (br s, 1H), 10.52 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 65 (548 mg, 94%) was obtained from 2′-nitroacetophenone=thiosemicarbazone (431 mg, 1.81 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.04 (s, 3H), 2.07 (s, 3H), 2.23 (s, 3H), 7.49-7.71 (m, 4H), 11.73 (br s, 1H)

Example 63 Compound 66

Step 1: In a manner similar to that in Step 1 of Example 1, 3′-nitroacetophenone=thiosemicarbazone (910 mg, 75%) was obtained from 3′-nitroacetophenone (661 mg, 4.00 mmol) and thiosemicarbazide (370 mg, 4.05 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.37 (s, 3H), 7.67 (br t, J=7.9 Hz, 1H), 8.16 (br s, 1H), 8.23 (br d, J=7.9 Hz, 1H), 8.40 (br s, 1H), 8.43 (br s, J=7.9 Hz, 1H), 8.61 (br s, 1H), 10.40 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 66 (409 mg, 60%) was obtained from 3′-nitroacetophenone=thiosemicarbazone (606 mg, 2.12 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.15 (s, 3H), 2.25 (s, 3H), 2.40 (s, 3H), 7.53 (br t, J=8.3 Hz, 1H), 7.73 (br d, J=8.3 Hz, 1H), 8.15 (br d, J=8.3 Hz, 1H), 8.30 (br s, 2H)

Example 64 Compound 67

Step 1: In a manner similar to that in Step 1 of Example 1, 4′-nitroacetophenone=thiosemicarbazone (475 mg, 94%) was obtained from 4′-nitroacetophenone (350 mg, 2.12 mmol) and thiosemicarbazide (195 mg, 2.13 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 67 (216 mg, 40%) was obtained from 4′-nitroacetophenone=thiosemicarbazone (397 mg, 1.67 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.15 (s, 3H), 2.24 (s, 3H), 2.38 (s, 3H), 7.59 (d, J=8.6 Hz, 2H), 8.20 (d, J=8.6 Hz, 2H), 8.30 (br s, 1H)

Example 65 Compound 68

Compound 61 (118 mg, 0.352 mmol) prepared in Example 58 was dissolved in methanol (5 mL), and to the solution was added potassium carbonate (200 mg, 1.48 mmol) and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. After the residue was dissolved in ethyl acetate, to the solution was added water and 1 mol/L hydrochloric acid, and the mixture was subjected to separation. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The resulting yellow oil was dissolved in methanol (3 mL). To the solution was added diisopropyl ether (10 mL), and the deposited crystals were collected by filtration and dried to obtain Compound 68 (96.9 mg, 94%).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 1.98 (s, 3H), 2.23 (s, 3H), 2.35 (s, 3H), 6.72 (br t, J=7.6 Hz, 1H), 6.83 (br d, J=7.6 Hz, 1H), 6.88 (br d, J=7.6 Hz, 1H), 7.10 (br t, J=7.6 Hz, 1H), 9.95 (br s, 1H), 11.45 (br s, 1H)

Example 66 Compound 69

In a manner similar to that in Example 65, Compound 69 (101 mg, 82%) was obtained from Compound 62 (140 mg, 0.417 mmol) prepared in Example 59.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.01 (s, 3H), 2.18 (s, 3H), 2.23 (s, 3H), 6.66 (br t, J=7.9 Hz, 1H), 6.69 (br s, 1H), 6.76 (br d, J=7.9 Hz, 1H), 7.13 (br t, J=7.9 Hz, 1H), 9.46 (br s, 1H), 11.60 (br s, 1H)

Example 67 Compound 70

In a manner similar to that in Example 65, Compound 70 (88 mg, 91%) was obtained from Compound 64 (110 mg, 0.328 mmol) prepared in Example 61.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.00 (s, 3H), 2.16 (s, 3H), 2.23 (s, 3H), 6.71 (d, J=8.6 Hz, 2H), 7.15 (d, J=8.6 Hz, 2H), 9.48 (br s, 1H), 11.6 (br s, 1H).

Example 68 Compound 71

Step 1: In a manner similar to that in Step 1 of Example 1, 3′-cyanoacetophenone=thiosemicarbazone (863 mg, 99%) was obtained from 3-acetylbenzonitrile (581 mg, 4.00 mmol) and thiosemicarbazide (370 mg, 4.05 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 71 (274 mg, 68%) was obtained from 3′-cyanoacetophenone=thiosemicarbazone (300 mg, 1.34 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.08 (s, 3H), 2.26 (s, 3H), 2.36 (s, 3H), 7.46 (m, 1H), 7.56 (m, 1H), 7.68 (m, 1H), 7.71 (br s, 1H), 8.73 (br s, 1H)

Example 69 Compound 72

Step 1: In a manner similar to that in Step 1 of Example 1, 4′-cyanoacetophenone=thiosemicarbazone (430 mg, 98%) was obtained from 4-acetylbenzonitrile (290 mg, 2.0 mmol) and thiosemicarbazide (185 mg, 2.02 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.30 (s, 3H), 7.82 (d, J=8.4 Hz, 2H), 8.12 (br s, 1H), 8.14 (d, J=8.4 Hz, 2H), 8.40 (br s, 1H), 10.51 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 72 (494 mg, 94%) was obtained from 4′-cyanoacetophenone=thiosemicarbazone (380 mg, 1.74 mmol) prepared above.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.01 (s, 3H), 2.18 (s, 3H), 2.31 (s, 3H), 7.54 (d, J=11.7 Hz, 2H), 7.81 (d, J=11.7 Hz, 2H), 11.73 (br s, 1H)

Example 70 Compound 73

Step 1: In a manner similar to that in Step 1 of Example 1, 3′-trifluoromethylacetophenone=thiosemicarbazone (888 mg, 63%) was obtained from 3′-trifluoromethylacetophenone (765 mg, 4.07 mmol) and thiosemicarbazide (370 mg, 4.05 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 73 (270 mg, 68%) was obtained from 3′-trifluoromethylacetophenone=thiosemicarbazone (300 mg, 1.15 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.01 (s, 3H), 2.27 (s, 3H), 2.37 (s, 3H), 7.43 (br t, J=7.6 Hz, 1H), 7.52 (br d, J=7.6 Hz, 1H), 7.63 (br d, J=7.6 Hz, 1H), 7.65 (br s, 1H), 8.89 (br s, 1H)

Example 71 Compound 74

Step 1: In a manner similar to that in Step 1 of Example 1, 2′-carboxyacetophenone=thiosemicarbazone (489 mg, 52%) was obtained from 2-acetylbenzoic acid (381 mg, 4.17 mmol) and thiosemicarbazide (381 mg, 4.17 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 74 (313 mg, 64%) was obtained from 2′-carboxyacetophenone=thiosemicarbazone (363 mg, 1.53 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.04 (s, 3H), 2.29 (s, 3H), 2.38 (s, 3H), 3.20-3.30 (br s, 1H), 4.88-8.15 (m, 3H), 8.32-8.33 (br m, 1H)

Example 72 Compound 75

Step 1: In a manner similar to that in Step 1 of Example 1, 2′,6′-dimethoxyacetophenone=thiosemicarbazone (747 mg, 83%) was obtained from 2′,6′-dimethoxyacetophenone (606 mg, 3.98 mmol) and thiosemicarbazide (374 mg, 4.09 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.09 (s, 3H), 3.77 (s, 6H), 6.80 (d, J=8.2 Hz, 2H), 7.44 (t, J=8.2 Hz, 1H), 7.83 (br s, 1H), 8.04 (br s, 1H), 8.31 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 75 (441 mg, 89%) was obtained from 2′,6′-diraethoxyacetophenone=thiosemicarbazone (363 mg, 1.61 mmol) prepared above.

¹H NMR (270 MHz, CDCl₆) δ (ppm): 2.02 (s, 3H), 2.21 (s, 3H), 2.51 (s, 3H), 3.78 (s, 6H), 6.53 (d, J=8.5 Hz, 2H), 7.15 (t, J=8.5 Hz, 1H), 8.70 (br s, 1H)

Example 73 Compound 76

Step 1: In a manner similar to that in Step 1 of Example 1, 3′,5′-dihydroxyacetophenone=thiosemicarbazone (707 mg, 78%) was obtained from 3′,5′-dihydroxyacetophenone (613 mg, 4.03 mmol) and thiosemicarbazide (376 mg, 4.11 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.20 (s, 3H), 6.25 (br s, 1H), 6.69 (br s, 2H), 7.64 (br s, 1H), 8.26 (br s, 1H), 9.29 (br s, 2H), 10.19 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 76 (591 mg, 69%) was obtained from 3′,5′-dihydroxyacetophenone=thiosemicarbazone (622 mg, 2.76 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.01 (s, 3H), 2.17 (s, 3H), 2.18 (s, 3H), 6.10 (br s, 1H), 6.16 (br s, 2H), 9.27 (br s, 2H), 11.59 (br s, 1H)

Example 74 Compound 77

Step 1: In a manner similar to that in Step 1 of Example 1, 3′,4′-dihydroxyacetophenone=thiosemicarbazone (747 mg, 83%) was obtained from 3′,4′-dihydroxyacetophenone (606 mg, 3.98 mmol) and thiosemicarbazide (374 mg, 4.09 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.20 (s, 3H), 6.72 (br d, J=8.3 Hz, 1H), 7.18 (br d, J=8.3 Hz, 1H), 7.29 (br s, 1H), 7.65 (br s, 1H), 8.18 (br s, 2H), 9.09 (br s, 2H), 10.09 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 77 (441 mg, 89%) was obtained from 3′,4′-dihydroxyacetophenone=thioseraicarbazone (363 mg, 1.61 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.01 (s, 3H), 2.06 (s, 3H), 2.20 (s, 3H), 6.62 (br t, J=7.6 Hz, 1H), 6.66 (br d, J=8.2 Hz, 1H), 6.71 (br s, 1H), 8.93 (s, 1H), 8.97 (s, 1H), 11.56 (br s, 1H)

Example 75 Compound 78

Step 1: In a manner similar to that in Step 1 of Example 1, 2′,4′-dimethylacetophenone=thiosemicarbazone (110 mg, 12%) was obtained from 2′,4′-dimethylacetophenone (598 mg, 4.04 mmol) and thiosemicarbazide (366 mg, 4.00 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 78 (107 mg, 77%) was obtained from 2′,4′-dimethylacetophenone=thiosemicarhazone (100 mg, 0.452 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.16 (s, 3H), 2.21 (s, 3H), 2.35 (s, 3H), 6.92 (d, J=7.9 Hz, 1H), 7.07 (d, J=7.9 Hz, 1H), 8.22 (br s, 1H)

Example 76 Compound 79

Step 1: To a solution of hydrazine monohydrate (1.00 mL, 20.6 mmol) in acetonitrile (5.00 mL) was added allyl isothiocyanate (2.00 mL, 20.4 mmol), and the mixture was stirred at 60° C. for 30 minutes. To the reaction mixture was added diethyl ether (50 mL), and the deposited solid was collected by filtration. The collected solid was dried to obtain 4-allylthiosemicarbazide (1.22 g, 46%).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 4.11 (t, J=5.3 Hz, 2H), 4.47 (br s, 2H), 5.03 (d, J=12.3 Hz, 1H), 5.08 (d, J=19.1 Hz, 1H), 5.86 (m, 1H), 7.88 (br s, 1H), 8.70 (br s, 1H)

Step 2: In a manner similar to that in Step 1 of Example 1, acetophenone=4-allylthiosemicarbazone (1.74 g, 80%) was obtained from acetophenone (1.09 mL, 9.34 mmol) and 4-allylthiosemicarbazide (1.22 g, 9.31 mmol) prepared above.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.31 (s, 3H), 4.25 (t, J=5.8 Hz, 2H), 5.10 (d, J=10.5 Hz, 1H), 5.18 (d, J=17.5 Hz, 1H), 5.91 (m, 1H), 7.37-7.42 (m, 3H), 7.91-7.94 (m, 2H), 8.61 (t, J=6.0 Hz, 1H), 10.3 (br s, 1H)

Step 3: Acetophenone=4-allylthiosemicarbazone (30 mg, 0.11 mmol) prepared above was dissolved in chloroform (0.5 mL), and to the solution was added acetyl chloride (0.17 mL, 2.32 mmol) and pyridine (0.190 mL, 2.31 mmol), and the solution was stirred at room temperature for 5 hours. To the reaction mixture was added 2 mol/L aqueous sodium hydroxide, then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/2) to obtain Compound 79 (25 mg, 89%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.26 (s, 3H), 2.27 (s, 3H), 2.36 (s, 3H), 4.47-4.53 (m, 2H), 5.24 (d, J=17.3 Hz, 1H), 5.29 (d, J=10.5 Hz, 1H), 5.91 (m, 1H), 7.20-7.45 (m, 5H)

FAB-MS (m/z): 318 (M⁺+1)

Example 77 Compounds 80 and 81

Step 1: In a manner similar to that in Step 3 of Example 76, Compound 80 (42 mg, 5%) was obtained from acetophenone=4-allylthiosemicarbazone (694 mg, 2.97 mmol) prepared in Step 2 of Example 76, isobutyryl chloride (0.63 mL, 5.97 mmol) and pyridine (0.43 mL, 5.26 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.10 (d, J=6.8 Hz, 3H), 1.13 (d, J=6.9 Hz, 3H), 2.39 (s, 3H), 3.25 (quin., J=7.0 Hz, 1H), 3.84-4.00 (m, 3H), 5.19 (d, J=10.2 Hz, 1H), 5.26 (d, J=17.2 Hz, 1H), 5.93 (m, 1H), 7.20-7.49 (m, 5H)

Step 2: In a manner similar to that in Example 15, Compound 81 (527 mg, 74%) was obtained from Compound 80 (623 mg, 2.05 mmol) prepared above, acetyl chloride (0.59 mL, 8.30 mmol) and pyridine (0.77 mL, 8.28 mmol).

¹H NMR (270 MHz, CDCl₆) δ (ppm): 1.10 (d, J=6.9 Hz, 3H), 1.12 (d, J=6.9 Hz, 3H), 2.27 (s, 3H), 2.34 (s, 3H), 3.21 (quin., J=6.9 Hz, 1H), 4.51 (br s, 2H), 5.25 (d, J=17.2 Hz, 1H), 5.30 (d, J=10.7 Hz, 1H), 5.93 (m, 1H), 7.20-7.42 (m, 5H)

AP-MS (m/z): 346 (M⁺+1)

Example 78 Compound 82

In a manner similar to that in Step 3 of Example 76, Compound 82 (269 mg, 47%) was obtained from acetophenone=thiosemicarbazone (306 mg, 1.59 mmol) prepared in Step 1 of Example 1, pivaloyl chloride (0.40 mL, 3.21 mmol) and pyridine (0.26 mL, 3.22 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.29 (s, 9H), 1.30 (s, 9H), 2.35 (s, 3H), 7.20-7.46 (m, 5H), 7.90 (m, 1H)

AP-MS (m/z): 360 (M⁺−1)

Example 79 Compounds 83 and 84

Step 1: In a manner similar to that in Example 12, Compound 83 (537 mg, 67%) was obtained from Compound 21(1.00 g, 2.88 mmol) prepared in Example 18.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.12 (d, J=6.9 Hz, 3H), 1.14 (d, J=6.9 Hz, 3H), 2.39 (s, 3H), 2.91 (d, J=4.9 Hz, 3H), 3.30 (m, 1H), 3.90 (br, 1H), 7.20-7.43 (m, 5H)

Step 2: In a manner similar to that in Example 15, Compound 84 (233 mg, 38%) was obtained from Compound 83 (536 mg, 1.93 mmol) prepared above, acetyl chloride (0.28 mL, 3.87 mmol) and pyridine (0.32 mL, 3.90 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.12 (d, J=6.9 Hz, 3H), 1.14 (d, J=6.9 Hz, 3H), 2.28 (s, 3H), 2.34 (s, 3H), 3.28 (quin., J=6.9 Hz, 1H), 3.46 (br s, 3H), 7.20-7.43 (m, 5H)

FAB-MS (m/z): 320 (M⁺+1)

Elemental analysis (C₁₆H₂₁N₃O₂S): Found (%) C; 60.16, H; 6.63, N; 13.15, Calcd. (%) C; 60.27, H; 6.73, N; 13.20

Example 80 Compound 85

In a manner similar to that in Step 2 of Example 1, Compound 85 (176 mg, 20%) was obtained from acetophenone=thiosemicarbazone (517 mg, 2.68 mmol) prepared in Step 1 of Example 1 and isobutyric anhydride (2.22 mL, 13.4 mmol).

¹H NMR (270 MHz, CDCl₃) δ ppm): 1.09 (d, J=2.6 Hz, 3H), 1.12 (d, J=2.6 Hz, 3H), 1.21 (d, J=2.6 Hz, 3H), 1.23 (d, J=2.6 Hz, 3H), 2.37 (s, 3H), 2.50 (quin., J=6.9 Hz, 1H), 3.20 (quin., J=6.9 Hz, 1H), 7.20-7.48 (m, 5H), 7.98 (br s, 1H)

AP-MS (m/s): 334 (M⁺+1)

Elemental analysis (C₁₇H₂₃N₃O₂S): Found (%) C; 61.23, H; 6.95, N; 12.60, Calcd. (%) C; 61.22, H; 6.93, N; 12.63

Example 81 Compounds 86 and 87

Step 1: In a manner similar to that in Example 11, Compound 86 (588 mg, 43%) was obtained from acetophenone=thiosemicarbazone (1.01 g, 5.22 mmol) prepared in Step 1 of Example 1, isobutyric anhydride (1.73 mL, 10.4 mmol) and pyridine (0.84 mL, 10.4 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.09 (d, J=6.9 Hz, 3H), 1.11 (d, J=6.9 Hz, 3H), 2.40 (s, 3H), 3.21 (quin., J=6.9 Hz, 1H), 4.12 (br s, 2H), 7.20-7.40 (m, 5H)

Step 2: In a manner similar to that in Example 15, Compound 87 (47 mg, 16%) was obtained from Compound 86 (256 mg, 0.97 mmol) prepared above and acetic anhydride (0.46 mL, 4.88 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.19 (d, J=6.9 Hz, 3H), 1.20 (d, J=6.9 Hz, 3H), 2.25 (s, 3H), 2.38 (s, 3H), 2.47 (quin., J=6.9 Hz, 1H), 7.20-7.50 (m, 5H)

Example 82 Compound 88

In a manner similar to that in Example 15, Compound 88 (53 mg, 8%) was obtained from Compound 14 (502 mg, 2.14 mmol) prepared in Example 11 and isobutyric anhydride (1.77 mL, 10.7 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.20 (d, J=6.9 Hz, 3H), 1.22 (d, J=6.9 Hz, 3H), 2.24 (s, 3H), 2.38 (s, 3H), 2.48 (quin., J=6.9 Hz, 1H), 7.20-7.46 (m, 5H), 8.08 (br s, 1H)

AP-MS (m/z): 306 (M⁺+1)

Example 83 Compound 89

In a manner similar to that in Example 15, Compound 89 (274 mg, 64%) was obtained from Compound 14 (303 mg, 1.29 mmol) prepared in Example 11, cyclopentanecarbonyl chloride (0.32 mL, 2.59 mmol) and pyridine (0.21 mL, 2.60 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.50-1.95 (m, 8H), 2.24 (s, 3H), 2.38 (s, 3H), 2.65 (quin., J=7.9 Hz, 1H), 7.20-7.45 (m, 5H), 8.04 (br s, 1H)

AP-MS (m/z): 330 (M⁺−1)

Elemental analysis (C₁₇H₂₁N₃O₂S.0.4H₂O): Found (%) C; 60.30, H; 6.49, N; 12.41, Calcd. (%) C; 60.45, H; 6.49, N; 12.05

Example 84 Compounds 90 and 91

Step 1: In a manner similar to that in Example 11, Compound 90 (123 mg, 13%) was obtained from acetophenone=thiosemicarbazone (507 mg, 2.63 mmol) prepared in Step 1 of Example 1, isovaleric anhydride (1.05 mL, 5.30 mmol) and pyridine (0.43 mL, 5.26 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 0.82-1.00 (m, 6H), 2.12 (quin., J=6.6 Hz, 1H), 2.38 (s, 3H), 2.45 (d, J=7.7 Hz, 2H), 4.34 (br, 2H), 7.20-7.48 (m, 5H)

Step 2: In a manner similar to that in Example 15, Compound 91 (128 mg, 98%) was obtained from Compound 91 (105 mg, 0.38 mmol) prepared above, isobutyryl chloride (0.08 mL, 0.76 mmol) and pyridine (0.06 mL, 0.80 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 0.92 (d, J=6.6 Hz, 1H), 0.93 (d, J=6.6 Hz, 1H), 1.18 (d, J=3.3 Hz, 1H), 1.21 (d, J=3.3 Hz, 1H), 2.13 (quin., J=6.6 Hz, 1H), 2.38 (s, 3H), 2.39-2.56 (m, 4H), 7.20-7.48 (m, 5H), 8.15 (br s, 1H)

Example 85 Compound 92

Step 1: To a solution of acetophenone (4.00 mL, 34.3 mmol) in ethanol (15 mL) was added hydrazine monohydrate (6.67 mL, 138 mmol), and the mixture was heated under reflux for 4 hours. After cooling, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/2) to obtain acetophenone=hydrazone (5.39 g, ˜100%).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 2.00 (s, 3H), 5.34 (br s, 2H), 7.22-7.60 (m, 5H)

¹³C NMR (300 MHz, CDCl₃) δ (ppm): 11.3, 125.1, 127.7, 127.9, 139.1, 146.7

Step 2: To a solution of ammonium thiocyanate (3.40 g, 44.6 mmol) in acetone (20 mL) was added acetyl chloride (2.80 mL, 37.1 mmol), and the mixture was stirred at 70° C. for 10 minutes. To the reaction mixture was added acetophenone=hydrazone (5.36 g, 40.0 mmol) prepared above, and the mixture was heated under reflux for 20 minutes. After the reaction mixture was cooled, saturated aqueous ammonium chloride was added to the mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/2) to obtain acetophenone=4-acetylthiosemicarbazone (148 mg, 2%).

¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 2.15 (s, 3H), 2.28 (s, 3H), 7.47-7.51 (m, 3H), 7.56-7.59 (m, 2H), 11.6 (br s, 1H), 13.6 (br s, 1H)

Step 3: In a manner similar to that in Step 3 of Example 76, Compound 92 (36 mg, 88%) was obtained from acetophenone=4-acetylthiosemicarbazone (30 mg, 0.13 mmol) prepared above, pivaloyl chloride (32 μL, 0.26 mmol) and pyridine (20 μL, 0.26 mmol).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 1.27 (s, 9H), 2.25 (s, 3H), 2.38 (s, 3H), 7.23-7.46 (m, 5H), 8.13 (br s, 1H)

¹³C NMR (300 MHz, CDCl₃) δ (ppm): 24.0, 27.2, 39.4, 80.5, 125.1, 128.0, 128.6, 143.0, 143.1, 169.0, 176.7

AP-MS (m/z): 318 (M⁺+1)

Example 86 Compound 93

In a manner similar to that in Step 2 of Example 1, Compound 93 (123 mg, 45%) was obtained from Compound 14 (201 mg, 0.853 mmol) prepared in Example 11 and pivaloyl chloride (0.21 mL, 1.71 mmol)

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.26 (s, 9H), 2.24 (s, 3H), 2.38 (s, 3H), 7.20-7.51 (m, 5H), 8.10 (br s, 1H)

AP-MS (m/z): 319 (M⁺+1)

Example 87 Compound 94

Step 1: In a manner similar to that in Step 1 of Example 1, propiophenone=thiosemicarbazone (759 mg, 88%) was obtained from propiophenone (382 mg, 4.18 mmol) and thiosemicarbazide (541 mg, 3.92 mmol).

Step 2: In a manner similar to that in Step 3 of Example 76, Compound 94 (270 mg, 58%) was obtained from propiophenone=thiosemicarbazone (256 mg, 1.24 mmol) prepared above, pivaloyl chloride (597 μL, 4.84 mmol) and pyridine (391 μL, 4.84 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.15 (dd, J=7.1, 7.3 Hz, 3H), 1.29 (s, 9H), 1.34 (s, 9H), 2.29 (qd, J=7.3, 14.6 Hz, 1H), 3.10 (qd, J=7.1, 14.6 Hz, 1H), 7.21-7.40 (m, 5H), 8.31 (br s, 1H)

AP-MS (m/z): 377 (M⁺+1)

Example 88 Compound 95

Step 1: 2-Aminoacetophenone hydrochloride (6.10 g, 35.5 mmol) was dissolved in dichloromethane (60 mL), and to the solution was added triethylamine (7.56 g, 74.9 mmol). The solution was cooled to 0° C., and to the solution was added methanesulfonyl chloride (2.84 mL, 36.5 mmol). The solution was stirred at the same temperature for 5 minutes, and then at room temperature for 2 hours. To the reaction mixture was added water and 1 mol/L hydrochloric acid, and the mixture was extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residue was suspended in chloroform (5 mL) and the suspension was stirred, and then, the resulted crystals were collected by filtration to obtain 2-(methylsulfonylamino)acetophenone (4.58 g, 57%).

Step 2: In a manner similar to that in Step 1 of Example 1, 2-(methylsulfonylamino)acetophenone=thiosemicarbazone (3.08 g, 51%) was obtained from 2-(methylsulfonylamino)acetophenone (4.58 g, 20.2 mmol) prepared above and thiosemicarbazide (1.84 g, 20.2 mmol).

Step 3: In a manner similar to that in Step 3 of Example 76, Compound 95 (1.81 g, 91%) was obtained from 2-(methylsulfonylamino)acetoplienone=thiosemicarbazone (1.31 g, 4.36 mmol) prepared above, pivaloyl chloride (2.10 g, 17.4 mmol) and pyridine (1.38 g, 17.4 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.30 (s, 9H), 1.36 (s, 9H), 2.97 (s, 3H), 3.98 (dd, J=5.3, 13.8 Hz, 1H), 4.64 (dd, J=8.5, 13.8 Hz, 1H), 5.10 (br dd, J=5.3, 8.5 Hz, 1H), 7.25-7.39 (m, 5H), 7.93 (br s, 1H)

AP-MS (m/z): 453 (M⁺−1)

Example 89 Compound 96

Step 1: In a manner similar to that in Step 1 of Example 1, 2-(methylsulfonylamino)acetophenone=4-methylthiosemicarbazone (122 mg) was obtained from 2-(methylsulfonylamino)acetophenone (209 mg, 0.98 mmol) prepared in Step 1 of Example 88 and 4-methylthiosemicarbazide (106 mg, 1.00 mmol).

Step 2: In a manner similar to that in Step 3 of Example 76, Compound 96 (68 mg, 15%) was obtained from 2-(methylsulfonylamino)acetophenone=4-methylthiosemicarbazone (122 mg, 0.41 mmol) obtained above, pivaloyl chloride (128 μL, 1.04 mmol) and pyridine (80 μL, 1.04 mmol).

¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 1.27 (s, 3H), 1.28 (s, 3H), 2.95 (s, 3H), 3.53 (s, 3H), 3.94 (dd, J=13.9, 6.4 Hz, 1H), 4.27 (dd, J=13.9, 7.9 Hz, 1H), 7.11 (t, J=7.2 Hz, 1H), 7.21-7.38 (m, 5H)

AP-MS (m/z): 467 (M⁺−1)

Example 90 Compound 97

Step 1: In a manner similar to that in Step 1 of Example 88, 2-(ethylsulfonylamino)acetophenone (367 mg, 39%) was obtained from 2-aminoacetophenone hydrochloride (714 mg, 4.16 mmol), triethylamine (1.45 mL, 10.4 mmol) and ethanesulfonyl chloride (0.434 mL, 4.58 mmol).

Step 2: In a manner similar to that in Step 1 of Example 1, 2-(ethylsulfonylamino)acetophenone=thiosemicarbazone (327 mg, 43%) was obtained from 2-(ethylsulfonylamino)acetophenone (367 mg, 1.61 mmol) prepared above and thiosemicarbazide (147 mg, 1.61 mmol).

Step 3: In a manner similar to that in Step 2 of Example 1, Compound 97 (39 mg, 25%) was obtained from 2-(ethylsulfonylamino)acetophenone=thiosemicarbazone (99 mg, 0.330 mmol), pivaloyl chloride (162 μL, 1.32 mmol) and pyridine (130 μL, 1.58 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.26 (s, 9H), 1.28 (t, J=7.8 Hz, 3H), 1.29 (s, 9H), 3.09 (m, 2H), 3.97 (dd, J=5.1, 13.5 Hz, 1H), 4.60 (dd, J=8.1, 13.5 Hz, 1H), 4.99 (br dd, J=5.1, 8.1 Hz, 1H), 7.25-7.38 (br s, 5H), 7.93 (br s, 1H)

Example 91 Compound 98

Step 1: In a manner similar to that in Step 1 of Example 1, 2-methoxyacetophenone=thiosemicarbazone (367 mg, 62%) was obtained from 2-methoxyacetophenone (288 mg, 1.92 mmol) and thiosemicarbazide (179 mg, 1.96 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 98 (132 mg, 59%) was obtained from 2-methoxyacetophenone=thiosemicarbazone (128 mg, 0.573 mmol) prepared above, pivaloyl chloride (211 μL, 1.72 mmol) and pyridine (152 μL, 1.88 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.28 (s, 9H), 1.32 (s, 9H), 3.51 (s, 3H), 4.36 (d, J=9.6 Hz, 1H), 4.48 (d, J=9.6 Hz, 1H), 7.24-7.38 (m, 5H), 7.88 (s, 1H)

AP-MS (m/z): 392 (M⁺+1)

Example 92 Compound 99

Step 1: Methane sulfonamide (0.476 g, 5.00 mmol) was dissolved in N,N-dimethylformamide (10 mL), and to the solution was added 60% sodium hydride (0.275 g, 5.00 mmol) and the mixture was stirred in a water bath for 20 minutes. To the reaction mixture was added 3-chloropropiophenone (843 mg, 5.00 mol). The mixture was stirred in a water bath for one hour, and further stirred at room temperature for 15 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=20/1) to obtain 3-(methylsulfonylamino)propiophenone (240 mg, 21%).

Step 2: In a manner similar to that in Step 1 of Example 1, 3-(methylsulfonylamino)propiophenone=thiosemicarbazone (219 mg, 45%) was obtained from 3-(methylsulfonylamino)propiophenone (388 mg, 1.71 mmol) prepared above and thiosemicarbazide (156 mg, 1.71 mmol).

Step 3: In a manner similar to that in Step 2 of Example 1, Compound 99 (218 mg, 86%) was obtained from 3-(methylsulfonylamino)propiophenone=thiosemicarbazone (200 mg, 0.696 mmol) obtained above, pivaloyl chloride (342 μL, 2.78 mmol) and pyridine (219 μL, 2.78 mmol).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 1.30 (s, 9H), 1.34 (s, 9H), 2.56-2.65 (m, 1H), 2.94 (s, 3H), 3.21-3.44 (m, 2H), 3.58-3.70 (m, 1H), 4.45 (br s, 1H), 7.28-7.37 (m, 5H), 7.97 (br s, 1H)

AP-MS (m/z): 467 (M−1)

Example 93 Compound 100

In a manner similar to that in Step 3 of Example 76, an oily compound was obtained from 3-(methylsulfonylamino)propiophenone=thiosemicarbazone (173 mg, 0.604 mmol) prepared in Step 2 of Example 92, isobutyryl chloride (316 μL 3.02 mmol) and pyridine (292 μL, 3.62 mmol). The oily compound was dissolved in methanol (10 mL). To the solution was added potassium carbonate (1.00 g, 7.24 mind), and the mixture was vigorously stirred for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated. And then, to the concentrate was added chloroform, water and 1.0 mol/L hydrochloric acid, and the solution was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (chloroform/methanol=20/1) to obtain Compound 100 (111 mg, 41%).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 0.99-1.07 (m, 12H), 2.55-2.66 (m, 2H), 2.80-3.00 (m, 1H), 2.89 (s, 3H), 3.05-3.17 (m, 1H), 3.24-3.38 (m, 2H), 7.15 (br t, J=5.9 Hz, 1H), 7.24-7.39 (m, 5H), 11.6 (br s, 1H)

Example 94 Compound 101

Step 1: In a manner similar to that in Step 1 of Example 88, 2-(trifluoroacetylamino)acetophenone (4.38 g, 59%) was obtained from 2-aminoacetophenone hydrochloride (5.47 g, 31.9 mmol), triethylamine (11.1 mL, 80.0 mmol) and trifluoroacetic anhydride (4.96 mL, 35.1 mmol).

Step 2: In a manner similar to that in Step 1 of Example 1, 2-(trifluoroacetylamino)acetophenone=thiosemicarbazone was obtained from 2-(trifluoroacetylamino)acetophenone (3.00 g, 13.0 mmol) prepared above and thiosemicarbazide (1.18 g, 13.0 mmol).

Step 3: In a manner similar to that in Step 3 of Example 76, Compound 101 (1.72 g, 28%) was obtained from 2-(trifluoroacetylamino)acetophenone=thiosemicarbazone prepared above, pivaloyl chloride (50 mmol, 6.16 mL) and pyridine (60.0 mmol, 4.85 mL).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.27 (s, 9H), 1.38 (s, 9H), 3.95 (dd, J=3.0, 13.5 Hz, 1H), 4.89 (dd, J=3.7, 13.5 Hz, 1H), 7.15 (br d, J=7.3 Hz, 2H), 7.30-7.40 (m, 3H), 7.92 (br a, 1H), 8.27 (br s, 1H)

AP-MS (m/z): 471 (M⁻−1)

Example 95 Compound 102

In a manner similar to that in Step 3 of Example 76, Compound 102 (64.6 mg, 39%) was obtained from 2-(methylsulfonylamino)acetophenone=thiosemicarbazone (100 mg, 0.333 mmol) prepared in Step 2 of Example 88, isobutyryl chloride (140 μL, 1.33 mmol) and pyridine (108 μL, 1.33 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.17 (d, J=6.9 Hz, 3H), 1.19 (d, J=6.9 Hz, 3H), 1.25 (d, J=6.9 Hz, 6H), 1.29 (d, J=6.9 Hz, 6H), 3.05 (s, 3H), 3.10-3.30 (m, 3H), 4.01 (dd, J=4.8, 14.2 Hz, 1H), 4.74 (dd, J=7.8, 14.2 Hz, 1H), 5.37 (br s, 1H), 7.26-7.40 (m, 5H)

Example 96 Compound 103

Compound 102 (40.0 mg, 0.0805 mg) prepared in Example 95 was dissolved in methanol (10 mL). To the solution was added potassium carbonate (1.00 g, 7.24 mmol), and the mixture was vigorously stirred for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated. Then, to the residue was added chloroform, 1 mol/L hydrochloric acid and water, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (chloroform/methanol=20/1) to obtain Compound 103 (24.2 mg, 84%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.13 (d, J=6.9 Hz, 3H), 1.18 (d, J=6.9 Hz, 3H), 1.21 (d, J=6.9 Hz, 3H), 1.23 (d, J=6.9 Hz, 3H), 2.50 (m, 1H), 2.90 (s, 3H), 3.27 (m, 1H), 3.98 (dd, J=5.0, 13.9 Hz, 1H), 4.60 (dd, J=8.2, 13.9 Hz, 1H), 5.35 (br dd, J=5.0, 8.2 Hz, 1H), 7.26-7.40 (m, 5H), 8.02 (br s, 1H)

Example 97 Compound 104

Step 1: In a manner similar to that in Step 1 of Example 1, 3-(dimethylamino)propiophenone=thiosemicarbazone (491 mg, 46%) was obtained from 3-(dimethylamino)propiophenone (910 mg, 4.26 mmol) and thiosemicarbazide (387 mg, 4.25 mmol).

Step 2: In a manner similar to that in Step 3 of Example 76, Compound 104 (116 mg, 33%) was obtained from 3-(dimethylamino)propiophenone=thiosemicarbazone (210 mg, 0.839 mmol) prepared above, pivaloyl chloride (496 μL, 3.78 mmol) and pyridine (326 μL, 3.78 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.29 (s, 9H), 1.31 (s, 9H), 2.23-2.29 (m, 1H), 2.26 (br s, 3H), 2.27 (br s, 3H), 2.46 (ddd, J=8.8, 4.3, 11.3 Hz, 1H), 2.87 (m, 1H), 3.31 (m, 1H), 7.20-7.36 (m, 5H), 7.90 (br s, 1H)

Example 98 Compound 105

Step 1: In a manner similar to that in Step 2 of Example 1, 3-carbomethoxypropiophenone=thiosemicarbazone (10.6 g, 94%) was obtained from 3-carbomethoxypropiophenone (8.13 g, 42.3 mmol) and thiosemicarbazide (3.86 g, 42.3 mmol).

Step 2: In a manner similar to that in Step 3 of Example 76, Compound 105 (9.70 g, 77%) was obtained from 3-carbomethoxypropiophenone=thiosemicarbazone (7.76 g, 29.2 mmol) prepared above, pivaloyl chloride (14.4 mL, 117 mmol) and pyridine (11.3 mL, 140 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.29 (s, 9H), 1.32 (s, 9H), 2.37 (m, 1H), 2.67 (m, 1H), 2.79 (m, 1H), 3.42 (m, 1H), 3.70 (s, 3H), 7.22-7.40 (m, 5H), 7.89 (br s, 1H)

Example 99 Compound 106

Sodium hydroxide (2.7 g, 67 mmol) was dissolved in water (23 mL). Subsequently, to the solution was added methanol (30 mL) and the solution was stirred. To the solution was added Compound 105 (9.65 g, 22.3 mmol) prepared in Example 98, and the mixture was stirred at room temperature for 5 hours. To the reaction mixture was added 1 mol/L hydrochloric acid (20 mL) and water (30 mL), and the deposited white crystals were collected by filtration. The resulting crystals were washed with water and diisopropyl ether, and then, dried under reduced pressure to obtain Compound 106 (8.92 g, 96%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.30 (s, 9H), 1.33 (s, 9H), 2.00-2.51 (br s, 1H), 2.44 (m, 1H), 2.66 (m, 1H), 2.88 (m, 1H), 3.44 (m, 1H), 7.23-7.40 (m, 5H), 7.92 (br s, 1H)

Example 100 Compound 107

Compound 106 (1.21 g, 2.88 mmol) prepared in Example 99 was cooled to 0° C. Oxalyl chloride (5 mL) was added to the compound, and the solution was allowed to react at 0° C. for 1 hour. The solvent was evaporated under reduced pressure, and the residue was dried in vacuo. To the residue was added tetrahydrofuran, and the mixture was stirred at 0° C. Then, to the reaction mixture was added 4 mol/L ammonia-methanol solution (5 mL, 20 mmol), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added 1 mol/L hydrochloric acid (20 mL) and water (30 mL), and extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, to the resulting residue was added diisopropyl ether, and then the deposited white crystals were collected by filtration. The resulting crystals were washed with water and diisopropyl ether, and then dried under reduced pressure to obtain Compound 107 (8.92 g, 96%).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 1.17 (s, 9H), 1.28 (s, 9H), 1.81-2.03 (m, 1H), 2.15-2.30 (m, 1H), 2.49-2.75 (m,1H), 2.95-3.20 (m, 1H), 6.80 (br s, 1H), 7.20-7.41 (m, 5H), 10.93 (br s, 2H)

Example 101 Compound 108

In a manner similar to that in Example 100, Compound 108 (65 mg, 60%) was obtained from Compound 106 (0.104 g, 0.248 mmol) prepared in Example 99, oxalyl chloride (5 mL), hydroxylamine hydrochloride (0.017 g, 0.245 mmol) and triethylamine (0.062 g, 0.614 mmol).

APCl-MS (m/z): 433 (M⁻−1)

Example 102 Compound 109

In a manner similar to that in Example 100, Compound 109 (1.08 g, 87%) was obtained from Compound 106 (1.20 g, 2.86 mmol) prepared in Example 99, oxalyl chloride (5 mL) and 4 mol/L methylamine-methanol solution (10 mL, 40 mmol).

AP-MS (m/z): 431 (M⁻−1)

Example 103 Compound 110

Step 1: In a manner similar to that in Step 1 of Example 1, 3-(dimethylaminocarbonyl)propiophenone=thiosemicarbazone (3.67 g, 79%) was obtained from 3-(dimethylaminocarbonyl)propiophenone (4.00 g, 18.7 mmol) and thiosemicarbazide (1.70 g, 18.7 mmol).

Step 2: In a manner similar to that in Step 3 of Example 76, Compound 110 (1.64 g, 49%) was obtained from 3-(dimethylaminocarbonyl)propiophenone=thiosemicarbazone (2.00 g, 7.99 mmol) prepared above, pivaloyl chloride (3.94 mL, 32.0 mmol) and pyridine (3.11 mL, 38.4 mmol).

AP-MS (m/z): 447 (M⁺+1)

Example 104 Compound 111

In a manner similar to that in Example 100, Compound 111 (480 mg, 84%) was obtained from Compound 106 (51.8 mg, 0.124 mmol) prepared in Example 99, oxalyl chloride (0.5 mL), ethanolamine (7.58 mg, 0.248 mmol) and triethylamine (18.8 mg, 0.186 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.29 (s, 9H), 1.33 (s, 9H), 2.16-2.25 (m, 1H), 2.65-2.79 (m, 2H), 3.33-3.44 (m, 3H), 3.72 (m, 2H), 6.18 (br s, 1H), 7.22-7.35 (m, 6H), 8.01 (br s, 1H)

Example 105 Compound 112

In a manner similar to that in Example 100, Compound 112 (400 mg, 68%) was obtained from Compound 106 (51.8 mg, 0.124 mmol) prepared in Example 99, oxalyl chloride (0.5 mL), n-butylamine (18.14 mg, 0.248 mmol) and triethylamine (18.8 mg, 0.186 mmol).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 0.92 (t, J=7.1 Hz, 3H), 1.25-1.60 (m, 4H), 1.29 (s, 9H), 1.33 (s, 9H), 2.16 (m, 1H), 2.69 (m, 2H), 3.25 (m, 2H), 3.67 (m, 1H), 5.62 (br s, 1H), 7.23-7.34 (m, 5H), 7.94 (br s, 1H)

Example 106 Compound 113

In a manner similar to that in Example 100, Compound 113 (50 mg, 81%) was obtained from Compound 106 (51.8 mg, 0.124 mmol) prepared in Example 99, oxalyl chloride (0.5 mL), cyclohexylamine (24.6 mg, 0.248 mmol) and triethylamine (18.8 mg, 0.186 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.05-1.50 (n, 6H), 1.28 (s, 9H), 1.33 (s, 9H), 1.65-1.80 (m, 2H), 1.85-1.95 (m, 2H), 2.14 (m, 1H), 2.65 (m, 2H), 3.37 (m, 1H), 3.38 (m, 1H), 5.50 (br s, 1H), 7.10-7.38 (m, 5H), 7.93 (br s, 1H)

Example 107 Compound 114

Step 1: In a manner similar to that in Step 1 of Example 1, 4-carbomethoxybutyrophenone=thiosemicarbazone (0.700 g, 88%) was obtained from 4-carbomethoxybutyrophenone (0.588 g, 2.85 mmol) and thiosemicarbazide (0.260 g, 2.85 mmol).

Step 2: In a manner similar to that in Step 3 of Example 76, Compound 114 (318 mg, 64%) was obtained from 4-carbomethoxybutyrophenone=thiosemicarbazone prepared above, pivaloyl chloride (0.549 mL, 4.45 mmol) and pyridine (0.431 mL, 5.34 mmol).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 1.29 (s, 9H), 1.32 (s, 9H), 1.51-1.60 (m, 1H), 2.10-2.30 (m, 2H), 2.44 (m, 2H), 3.03-3.17 (n, 1H), 3.68 (s, 3H), 7.20-7.36 (m, 5H), 7.95 (br s, 1H)

Example 108 Compound 115

In a manner similar to that in Example 99, Compound 115 (234 mg, 95%) was obtained from Compound 114 (254 mg, 0.567 mmol) prepared in Example 107, sodium hydroxide (70.0 mg, 1.75 mmol), water (2 mL) and ethanol (4 mL).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.29 (s, 9H), 1.32 (s, 9H), 1.65-1.75 (m, 1H), 2.10-2.35 (m, 2H), 2.50 (m, 2H), 3.10-3.20 (m, 1H), 7.23-7.35 (m, 6H), 7.92 (br, s, 1H)

Example 109 Compound 116

In a manner similar to that in Example 100, Compound 116 (0.028 g, 55%) was obtained from Compound 115 (50.0 mg, 0.115 mmol) prepared in Example 108, oxalyl chloride (0.5 mL) and 40% methylamine-methanol solution (5 mL).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.29 (s, 9H), 1.32 (s, 9H), 1.50-1.65 (m, ¹H), 2.21-2.35 (m, 4H), 2.80 (d, J=4.8 Hz, 3H), 3.13 (m, 1H), 5.71 (br s, 1H) 7.20-7.35 (m, 5H), 7.97 (br s, 1H)

Example 110 Compound 117

In a manner similar to that in Example 100, Compound 117 (0.024 g, 47%) was obtained from Compound 115 (51.5 mg, 0.119 mmol) prepared in Example 108, oxalyl chloride (0.5 mL) and 4 mol/L ammonia-methanol solution (5 mL).

AP-MS (m/z): 431 (M⁻−1)

Example 111 Compound 118

In a manner similar to that in Step 3 of Example 76, Compound 118 (302 mg, 26%) was obtained from 2-(methylsulfonylamino)acetophenone=thiosemicarbazone (1.00 g, 3.49 mmol) prepared in Step 2 of Example 88, acetic anhydride (659 μL, 6.98 mmol) and pyridine (565 μL, 6.98 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.29 (s, 3H), 2.99 (s, 3H), 4.04 (d, J=14.0 Hz, 1H), 4.55 (d, J=14.0 Hz, 1H), 7.30-7.41 (m, 5H)

AP-MS (m/z): 329 (M⁺+1)

Example 112 Compound 119

Compound 118 (10.6 mg, 0.0323 mmol) prepared in Example 111 was dissolved in tetrahydrofuran (80 mL). To the solution was added dimethylaminopyridine (7.9 mg, 0.0646 mmol) and pyridine (7.8 μL, 0.0969 mmol), and the mixture was cooled to 0° C. To the solution was added pivaloyl chloride (20 μL, 0.162 mmol), and the mixture was stirred at 0° C. for 5 minutes, and further Stirred at room temperature for 4 hours. To the reaction mixture was added water and 1 mol/L hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (chloroform/methanol=12/1) to obtain Compound 119 (5.3 mg, 40%).

¹H-NMR (270 MHz, CDCl₃) δ (ppm): 1.27 (s, 9H), 2.32 (s, 3H), 2.95 (s, 3H), 3.98 (dd, J=5.2, 14.0 Hz, 1H), 4.60 (dd, J=8.1, 13.9 Hz, 1H), 5.40 (m, 1H), 7.29-7.40 (m, 5H), 8.11 (br s, 1H)

Example 113 Compound 120

2-(Methylsulfonylamino)acetophenone=thiosemicarbazone (300 mg, 1.05 mmol) prepared in Step 2 of Example 88 was dissolved in tetrahydrofuran (18 mL). To the solution was added 4-dimethylaminopyridine (641 mg, 5.25 mmol) and pivaloyl chloride (0.13 mL, 1.1 mmol), and the mixture was stirred at room temperature. To the mixture was further added, after 1 hour and after 2 hours each, pivaloyl chloride (0.065 mL, 0.53 mmol), and the mixture was stirred for 3.6 hours in total. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (chloroform/methanol=20/1) to obtain Compound 120 (88 mg, yield 22%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.34 (s, 9H), 2.96 (s, 3H), 4.06 (dd, J=6.2, 13.7 Hz, 1H), 4.19 (br s, 2H), 4.58 (dd, J=7.0, 13.7 Hz, 1H), 5.20 (t, J=6.4 Hz, 1H), 7.27-7.55 (m, 5H)

AP-MS (m/z): 371 (M⁺+1)

Example 114 Compound 121

6-Bromohexanoic acid (469 mg, 2.41 mmol) was dissolved in dichloromethane (15 mL). To the solution was added oxalyl chloride (0.28 mL, 3.2 mmol), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated from the reaction mixture under reduced pressure, and the resulting residue was dissolved in dichloromethane (15 mL). To the solution was added Compound 120 (297 mg, 0.802 mmol) prepared in Example 113 and pyridine (0.20 mL, 2.4 mmol), and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (chloroform/methanol=30/1) to obtain Compound 121 (315 mg, yield 72%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.32 (s, 9H), 1.50 (m, 2H), 1.67 (m, 2H), 1.86 (q, J=6.7 Hz, 2H), 2.34 (t, J=7.3 Hz, 2H), 2.98 (s, 3H), 3.40 (t, J=6.6 Hz, 2H), 3.99 (dd, J=5.2, 13.6 Hz, 1H), 4.63 (dd, J=8.2, 13.6 Hz, 1H), 5.24 (dd, J=5.5, 7.9 Hz, 1H), 7.26-7.38 (m, 5H), 8.40 (br s, 1H)

AP-MS (m/z): 547 (M⁺+1)

Example 115 Compound 122

Compound 121 (315 mg, 0.575 mmol) prepared in Example 114 was dissolved in N,N-diethylformamide (9.5 mL). To the solution was added sodium azide (187 mg, 2.88 mmol), and the mixture was stirred at 80° C. for 2 hours. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (hexane/ethyl acetate=1/2) to obtain Compound 322 (211 mg, yield 72%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.32 (s, 9H), 1.42 (m, 2H), 1.55-1.74 (m, 4H), 2.35 (t, J=7.3 Hz, 2H), 2.97 (s, 3H), 3.28 (t, J=6.7 Hz, 2H), 4.13 (dd, J=7.2, 14.3 Hz, 1H), 4.63 (dd, J=8.3, 13.5 Hz, 1H), 5.21 (dd, J=5.2, 8.0 Hz, 1H), 7.26-7.38 (m, 5H), 8.37 (s, 1H)

AP-MS (m/z): 510 (M⁺+1)

Example 116 Compound 123

Compound 122 (23.6 mg, 0.0463 mmol) prepared in Example 115 was dissolved in tetrahydrofuran (1.0 mL). To the solution was added triphenylphosphine (36.4 mg, 0.139 mmol), and the mixture was stirred at room temperature for 25 minutes. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative -thin layer chromatography (chloroform/methanol/ammonia=5/0.8/0.2) to obtain Compound 123 (7.1 mg, yield 32%).

¹H-NMR (270 MHz, CDCl₃) δ (ppm): 1.31 (s, 9H), 1.47 (m, 2H), 1.57 (m, 2H), 1.70 (m, 2H), 2.39 (m, 2H), 2.82 (m, 2H), 2.97 (s, 3H), 3.95 (d, J=13.7 Hz, 1H), 4.14 (br s, 3H), 4.65 (d, J=13.5 Hz, 1H), 7.24-7.35 (m, 5H)

AP-MS (m/z): 484 (M⁺+1)

Example 117 Compound 124

Compound 123 (5.0 mg, 0.010 mmol) prepared in Example 116 was dissolved in dichloromethane (0.4 mL). To the solution was added pyridine (0.0025 mL, 0.031 mmol) and acetyl chloride (0.0015 mL, 0.021 mmol), and the mixture was stirred at room temperature for 0.8 hour. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (chloroform/methanol=20/1) to obtain Compound 124 (3.9 mg, yield 72%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.32 (s, 9H), 1.37 (m, 2H), 1.53 (m, 2H), 1.69 (m, 2H), 1.98 (s, 3H), 2.39 (t, J=7.4 Hz, 2H), 2.97 (s, 3H), 3.24 (m, 2H), 3.98 (dd, J=5.2, 13.6 Hz, 1H), 4.64 (dd, J=8.2, 13.5 Hz, 1H), 5.22 (dd, J=5.4, 8.2 Hz, 1H), 5.68 (m, 1H), 7.24-7.38 (m, 5H), 9.08 (s, 1H)

FAB-MS (m/z): 526 (M⁺+1)

Example 118 Compound 125

Step 1: In a manner similar to that in Step 1 of Example 1, 3′-hydroxyacetophenone=4-ethylthiosemicarbazone (342 mg, 70%) was obtained from 3′-hydroxyacetophenone (279 mg, 2.05 mmol) and 4-ethylthiosemicarbazide (242 mg, 2.03 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 125 (90 mg, 60%) was obtained from 3′-hydroxyacetophenone=4-ethylthiosemicarbazone (200 mg, 0.843 mmol) prepared above, acetic anhydride (260 mg, 2.53 mmol) and pyridine (108 μL, 1.34 mmol).

¹11 NMR (270 MHz, CDCl₃) δ (ppm): 2.02 (s, 3H), 2.20 (s, 3H), 2.28 (s, 3H), 2.30 (t, J=8.4 Hz, 3H), 2.36 (s, 3H), 3.30-3.47 (br s, 2H), 7.20-7.40 (m, 5H)

Example 119 Compound 126

In a manner similar to that in Example 65, Compound 126 (81 mg, 49%) was obtained from Compound 125 (187 mg, 0.515 mg) prepared in Example 118, methanol (10 mL) and potassium carbonate (1.00 g, 7.24 mmol)

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.01 (s, 3H), 2.18 (s, 3H), 2.23 (s, 3H), 2.29 (t, J=8.4 Hz, 3H), 3.40 (br s, 2H), 6.65-6.80 (m, 3H), 7.13 (m, 1H), 11.6 (br s, 1H)

Example 120 Compound 127

Compound 69 (50.5 mg, 0.172 mmol) prepared in Example 66 was dissolved in dichloromethane (0.5 mL). To the solution was added triethylamine (17.4 mg, 0.172 mmol) and ethyl isocyanate (13.6 μL, 0.172 mmol), and the mixture was stirred at room temperature for 12 hours. To the reaction mixture was added 1 mol/L hydrochloric acid and water, and the mixture was subjected to separation. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (chloroform/methanol/water=90/10/1) to obtain Compound 127 (53.3 mg, 85%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.21 (t, J=7.0 Hz, 3H), 2.09 (s, 3H), 2.22 (s, 3H), 2.35 (s, 3H), 3.31 (n, 2H), 5.03 (br s, 1H), 7.06 (br d, J=8.4 Hz, 1H), 7.24-7.35 (m, 3H), 8.41 (br s, 1H)

Example 121 Compound 128

In a manner similar to that in Step 3 of Example 76, Compound 128 (500 mg, 63%) was obtained from 3′-hydroxyacetophenone=thiosemicarbazone (398 mg, 1.90 mmol) prepared in Step 1 of Example 59, isobutyryl chloride (1.56 mL, 7.60 mmol) and pyridine (721 mg, 9.12 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.09 (d, J=6.8 Hz, 3H), 1.10 (d, J=6.8 Hz, 3H), 1.21 (d, J=6.8 Hz, 3H), 1.22 (d, J=6.8 Hz, 3H), 1.29 (d, J=7.3 Hz, 6H), 2.34 (s, 3H), 2.51 (m, 1H), 2.78 (m, 1H), 3.18 (m, 1H), 7.00 (br d, J=7.3 Hz, 1H), 7.13 (br s, 1H), 7.25-7.33 (m, 2H), 7.93 (br s, 1H)

Example 122 Compound 129

In a manner similar to that in Example 65, Compound 129 (298 mg, 85%) was obtained from Compound 128 (420 mg, 1.00 mmol) prepared in Example 121 and potassium carbonate (1.00 g, 7.24 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.11 (d, J=7.0 Hz, 3H), 1.12 (d, J=7.0 Hz, 3H), 1.22 (d, J=7.0 Hz, 3H), 1.23 (d, J=7.0 Hz, 3H), 2.23 (s, 3H), 2.51 (m, 1H), 3.20 (m, 1H), 5.60 (br s, 1H), 6.63 (br d, J=7.3 Hz, 1H), 6.85 (br s, 1H), 6.94 (br d, J=7.9 Hz, 1H), 7.15 (br t, J=7.9 Hz, 1H), 8.00 (br s, 1H)

Example 123 Compound 130

In a manner similar to that in Step 3 of Example 76, Compound 130 (389 mg, 88%) was obtained from 2′-chloroacetophenone=thiosemicarbazone (253 mg, 1.11 mmol) prepared in Step 1 of Example 53, pivaloyl chloride (546 μL, 4.44 mmol) and pyridine (389 μL, 4.80 mmol). ¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.29 (s, 9H), 1.30 (s, 9H), 2.35 (s, 3H), 7.20-7.27 (m, 2H), 7.35-7.43 (m, 2H), 7.95 (br s, 1H)

Example 124 Compound 131

In a manner similar to that in Step 3 of Example 76, Compound 131 (389 mg, 86%) was obtained from 2′-chloroacetophenone=thiosemicarbazone (400 mg, 1.89 mmol) prepared in Step 1 of Example 53, isobutyryl chloride (594 μL, 5.67 mmol) and pyridine (538 mg, 6.80 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.10 (d, J=6.6 Hz, 3H), 1.12 (d, J=6.6 Hz, 3H), 1.23 (d, J=6.9 Hz, 2H), 1.25 (d, J=6.9 Hz, 3H), 2.39 (s, 3H), 2.52 (m, 1H), 3.18 (m, 1H), 7.22-7.28 (m, 2H), 7.37-7.45 (m, 2H), 7.96 (br s, 1H)

Example 125 Compound 132

Step 1: In a manner similar to that in Step 1 of Example 1, 1-(5-bromo-2-thienyl)ethanone=thiosemicarbazone (7.33 mg, 86%) was obtained from 1-(5-bromo-2-thienyl)ethanone (630 mg, 3.07 mmol) and thiosemicarbazide (281 mg, 3.07 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 132 (158 mg, 58%) was obtained from 1-(5-bromo-2-thienyl)ethanone=thiosemicarbazone (2.11 mg, 0.758 mmol) prepared above and acetic anhydride (10 mL).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.15 (s, 3H), 2.19 (s, 3H), 2.36 (s, 3H), 6.84 (br s, 1H), 6.86 (br s, 1H), 8.29 (br s, 1H)

Example 126 Compound 133

Step 1: In a manner similar to that in Step 1 of Example 1, 1-(3-bromo-2-thienyl)ethanone=thiosemicarbazone was obtained from 1-(3-bromo-2-thienyl)ethanone (108 mg, 0.388 mmol) and thiosemicarbazide (36.5 mg, 0.399 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 133 (139 mg, 99%) was obtained from 1-(3-bromo-2-thienyl)ethanone=thiosemicarbazone prepared above and acetic anhydride (10 mL).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.04 (s, 3H), 2.14 (s, 3H), 2.23 (s, 3H), 2.41 (s, 3H), 6.96 (br s, 1H), 7.17 (br s, 1H), 9.08 (br s, 1H)

Example 127 Compound 134

Step 1: In a manner similar to that in Step 1 of Example 1, 1-(3-chloro-2-thienyl)ethanone=thiosemicarbazone was obtained from 1-(3-chloro-2-thienyl)ethanone (137 mg, 0.853 mmol) and thiosemicarbazide (78 mg, 0.853 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 134 (158 mg, 58%) was obtained from 1-(3-chloro-2-thienyl)ethanone=thiosemicarbazone prepared above and acetic anhydride (10 mL).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.14 (s, 3H), 2.21 (s, 3H), 2.43 (s, 3H), 6.89 (d, J=5.3 Hz, 1H), 7.18 (d, J=5.3 Hz, 1H), 8.28 (br s, 1H)

Example 128 Compound 135

Step 1: In a manner similar to that in Step 1 of Example 1, 1-(3-chloro-2-thienyl)ethanone=thiosemicarbazone (96.1 mg, 71%) was obtained from 1-(3-chloro-2-thienyl)ethanone (92.9 tag, 0.578 mmol) and thiosemicarbazide (52.9 mg, 0.578 mmol).

Step 2: In a manner similar to that in Step 3 of Example 76, Compound 134 (90 mg, 60%) was obtained from 1-(3-chloro-2-thienyl)ethanone=thiosemicarbazone (86.9 mg, 0.372 mmol) prepared above, pivaloyl chloride (138 μL, 1.12 mmol) and pyridine (108 μL, 1.34 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.33 (s, 9H), 1.35 (s, 9H), 2.43 (s, 3H), 6.90 (d, J=6.3 Hz, 1H), 7.20 (d, J=6.3 Hz, 1H), 7.97 (br s, 1H)

Example 129 Compound 136

Compound 14 (41 mg, 0.17 mmol) prepared in Example 11 was dissolved in acetonitrile (0.5 mL). To the solution was added di-tert-butyl dicarbonate (0.114 mg, 0.522 mmol) and DMAP (43 mg, 0.35 mmol), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (chloroform/methanol=20/1) to obtain Compound 136 (24 mg, 41%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.47 (s, 9H), 2.21 (s, 3H), 2.40 (s, 3H), 7.14-7.48 (m, 6H)

AP-MS (m/z): 334 (M⁻−1)

Example 130 Compound 137

Compound 14 (74 mg, 0.31 mmol) prepared in Example 11 was dissolved in N,N-dimethylformamide (2 mL). To the solution was added 60% sodium hydride (50 mg, 1.3 mmol) and dimethylcarbamoyl chloride (0.116 mL, 1.26 mmol), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (chloroform/methanol=40/1, then ethyl acetate/n-hexane=3/1) to obtain Compound 137 (44 mg, 46%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.23 (s, 3H), 2.37 (s, 3H), 3.00 (s, 6H), 7.20-7.45 (m, 5H)

AP-MS (m/z): 307 (M⁺+1)

Example 131 Compound 138

Step 1: Copper (II) bromide (130 mg, 0.583 mmol) was dissolved in acetonitrile (5.4 mL). To the solution was added 4A-butyl nitrite (0.093 mL, 0.78 mmol) under ice cooling. After being stirred for 10 minutes, to the mixture was added Compound 14 (180 mg, 0.486 mmol) prepared in Example 11, and the mixture was stirred for 1 hour with gradually raising the temperature up to room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/18) to obtain 3-acetyl-5-bromo-2-methyl-2-phenyl-1,3,4-thiadialine (145 mg, 84%).

Step 2: 3-Acetyl-5-bromo-2-methyl-2-phenyl-1,3,4-thiadialine (50 mg, 0.17 mmol) prepared above was dissolved in dichloromethane (0.5 mL). To the solution was added piperidine (0.033 mL, 0.33 mmol), and the mixture was stirred at room temperature for 20 minutes. To the reaction mixture was further added piperidine (0.165 mL, 1.67 mmol), and the mixture was stirred at the same temperature for 5.5 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (chloroform) to obtain Compound 138 (12 mg, 24%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.60 (m, 6H), 2.25 (s, 3H), 2.40 (s, 3H), 3.24 (m, 4H), 7.20-7.39 (m, 3H), 7.45 (m, 2H)

AP-MS (m/z): 304 (M⁺+1)

Example 132 Compound 139

In a manner similar to that in Step 2 of Example 131, Compound 139 (38 mg. 59%) was obtained from 3-acetyl-5-bromo-2-methyl-2-phenyl-1,3,4-thiadiallyn (61 mg, 0.20 mmol) prepared in Step 1 of Example 131 and 4-methylpiperidine (0.483 mL, 4.08 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 0.96 (d, J=6.4 Hz, 3H), 1.25 (m, 2H), 1.44-1.71 (m, 3H), 2.25 (s, 3H), 2.40 (s, 3H), 2.88 (m, 2H), 3.61 (m, 2H), 7.20-7.49 (m, 3H), 7.46 (m, 2H)

AP-MS (m/z): 318 (M⁺+1)

Example 133 Compound 140

Compound 118 (50 mg, 0.15 mmol) prepared in Example 111 was dissolved in dichloromethane (2 mL). To the solution was added pyridine (0.031 mL, 0.38 mmol) and hexanoyl chloride (0.053 mL, 0.38 mmol), and the mixture was stirred at room temperature for 2.5 hours. To the reaction mixture was further added pyridine (0.012 mL, 0.15 mmol) and hexanoyl chloride (0.021 mL, 0.15 mmol), and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (chloroform/methanol=15/1) to obtain Compound 140 (52 nag, 80%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 0.90 (t, J=6.6 Hz, 3H), 1.22-1.41 (m, 4H), 1.64 (m, 2H), 2.31 (s, 3H), 2.32 (t, J=7.5 Hz, 2H), 2.96 (s, 3H), 3.98 (dd, J=5.4, 13.9 Hz, 1H), 4.60 (dd, J=8.1, 13.9 Hz, 1H), 5.38 (dd, J=5.4, 8.1 Hz, 1H), 7.20-7.44 (m, 5H), 8.02 (s, 1H)

AP-MS (m/z): 427 (M⁺+1)

Example 134 Compound 141

In a manner similar to that in Example 133, Compound 141 (22 mg, 18%) was obtained from Compound 118 (100 mg, 0.305 mmol) prepared in Example 111, pyridine (0.062 mL, 0.78 mmol) and crotonoyl chloride (0.075 mL, 0.78 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.91 (dd, J=1.7, 7.0 Hz, 3H), 2.32 (s, 3H), 2.97 (s, 3H), 3.99 (dd, J=5.6, 13.9 Hz, 1H), 4.61 (dd, J=7.6, 13.9 Hz, 1H), 5.51 (dd, J=5.6, 7.6 Hz, 1H), 5.86 (dd, J=1.7, 15.2 Hz, 1H), 7.03 (dd, J=7.0, 15.2 Hz, 1H), 7.22-7.41 (m, 5H), 8.49 (s, 1H)

AP-MS (m/z): 397 (M⁺+1)

Example 135 Compound 142

In a manner similar to that in Example 133, Compound 142 (42 mg, 70%) was obtained from Compound 118 (50 mg, 0.15 mmol) prepared in Example 111, pyridine (0.062 mL, 0.76 mmol) and cyclopropanecarbonyl chloride (0.070 mL, 0.76 mmol).

¹H NMR (270 MHz, CD₃OD) δ (ppm): 0.87-0.98 (m, 4H), 1.77 (m, 1H), 2.28 (s, 3H), 3.01 (s, 3H), 3.97 (d, J=14.0 Hz, 1H), 4.55 (d, J=14.0 Hz, 1H), 7.22-7.42 (m, 5H)

AP-MS (m/z): 397 (M⁺+1)

Example 136 Compound 143

In a manner similar to that in Example 133, Compound 143 (24 mg, 22%) was obtained from Compound 118 (80 mg, 0.24 mmol) prepared in Example 111, pyridine (0.069 mL, 0.85 mmol) and 2-acetoxyisobutyryl chloride (0.12 mL, 0.85 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.65 (s, 3H), 1.67 (s, 3H), 2.15 (s, 3H), 2.32 (s, 3H), 2.97 (s, 3H), 3.99 (dd, J=5.5, 14.0 Hz, 1H), 4.61 (dd, J=8.1, 14.0 Hz, 1H), 5.39 (dd, J=5.5, 8.1 Hz, 1H), 7.29-7.46 (m, 5H), 8.53 (s, 1H)

AP-MS (m/z): 457 (M⁺+1)

Example 137 Compound 144

Compound 143 (21 mg, 0.045 mmol) prepared in Example 136 was dissolved in a mixed solvent of methanol (1.6 mL) and water (0.8 mL). To the solution was added lithium hydroxide (11 mg, 0.45 mmol), and the mixture was stirred at room temperature for 3.5 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (chloroform/methanol=9/1) to obtain Compound 144 (11 mg, 56%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.44 (s, 3H), 1.48 (s, 3H), 2.32 (s, 3H), 2.85 (br s, 1H), 2.97 (s, 3H), 3.98 (dd, J=5.6, 13.9 Hz, 1H), 4.63 (dd, J=7.8, 13.9 Hz, 1H), 5.53 (dd, J=5.6, 7.8 Hz, 1H), 7.25-7.42 (m, 5H), 9.36 (s, 1H)

AP-MS (m/z): 415 (M⁺+1)

Example 138 Compound 145

In a manner similar to that in Example 133, Compound 145 (53 mg, 86%) was obtained from Compound 118 (50 mg, 0.15 mmol) prepared in Example 111, pyridine (0.031 mL, 0.38 mmol) and methoxyacetyl chloride (0.035 mL, 0.38 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.32 (s, 3H), 2.96 (s, 3H), 3.49 (s, 3H), 4.00 (s, 2H), 4.00 (dd, J=5.8, 13.9 Hz, 1H), 4.61 (dd, J=7.8, 13.9 Hz, 1H), 5.46 (dd, J=5.8, 7.8 Hz, 1H), 7.25-7.44 (m, 5H), 8.94 (s, 1H)

AP-MS (m/z): 401 (M⁺+1)

Example 139 Compound 146

In a manner similar to that in Example 133, Compound 146 (105 mg, 85%) was obtained from Compound 118 (100 mg, 0.305 mmol) prepared in Example 111, pyridine (0.062 mL, 0.76 mmol) and chloroacetyl chloride (0.061 mL, 0.76 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.34 (s, 3H), 2.97 (s, 3H), 4.02 (dd, J=5.6, 14.0 Hz, 1H), 4.11 (d, J=15.9 Hz, 1H), 4.18 (d, J=15.9 Hz, 1H), 4.62 (dd, J=7.8, 14.0 Hz, 1H), 5.28 (dd, J=5.6, 7.8 Hz, 1H), 7.22-7.43 (m, 5H), 8.87 (s, 1H)

AP-MS (m/z): 405 (M⁺+1)

Example 140 Compound 147

Compound 146 (50 mg, 0.12 mmol) prepared in Example 139 was dissolved in methanol (1 mL). To the solution was added 50% aqueous dimethylamine (0.033 and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was further added 50% aqueous dimethylamine (0.033 mL), and the mixture was stirred at the same temperature for 1.5 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (chloroform/acetone=1/1) to obtain Compound 147 (20 mg, 39%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.34 (s, 3H), 2.38 (s, 6H), 2.96 (s, 3H), 3.06 (d, J=17.3 Hz, 1H), 3.10 (d, J=17.3 Hz, 1H), 4.00 (d, J=13.9 Hz, 1H), 4.61 (d, J=13.9 Hz, 1H), 5.36 (br, 1H), 7.25-7.41 (m, 5H)

AP-MS (m/z): 414 (M⁺+1)

Example 141 Compound 148

In a manner similar to that in Example 133, Compound 148 (304 mg, 74%) was obtained from Compound 118 (297 mg, 0.903 mmol) prepared in Example 111, pyridine (0.183 mL, 2.26 mmol) and methyl 4-(chloroformyl)butyrate (0.312 mL, 2.26 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.00 (m, 2H), 2.32-2.56 (m, 4H), 2.34 (s, 3H), 2.99 (s, 3H), 3.71 (s, 3H), 4.01 (dd, J=5.4, 13.9 Hz, 1H), 4.63 (dd, J=7.9, 13.9 Hz, 1H), 5.45 (m, 1H), 7.21-7.49 (m, 5H), 8.54 (s, 1H)

AP-MS (m/z): 457 (M⁺+1)

Example 142 Compound 149

In a manner similar to that in Example 137, after Compound 148 (262 mg, 0.573 mmol) prepared in Example 141 was treated with lithium hydroxide monohydrate (206 mg, 4.91 mmol), to the reaction mixture was added ice and 0.5 mol/L hydrochloric acid, and the mixture was extracted with a mixed solvent of chloroform and methanol. After the extract was concentrated, the residue was purified by silica gel column chromatography (chloroform/methanol=43/7) to obtain Compound 149 (222 mg, 88%).

¹H NMR (270 MHz, CD₃OD) δ (ppm): 1.89 (m, 2H), 2.28 (s, 3H), 2.33 (t, J=7.3 Hz, 2H), 2.43 (t, J=7.5 Hz, 2H), 3.01 (s, 3H), 3.99 (d, J=14.0 Hz, 1H), 4.56 (d, J=14.0 Hz, 1H), 7.20-7.45 (m, 5H)

AP-MS (m/z): 441 (M⁻−1)

Example 143 Compound 150

Compound 149 (83 mg, 0.19 mmol) prepared in Example 142 was dissolved in 1,2-dichloroethane (3.2 mL). To the solution was added thionyl chloride (3.2 mL), and the mixture was stirred at 60° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and then the residue was purified by preparative thin layer chromatography (chloroform/methanol=20/1) to obtain Compound 150 (61 mg, 76%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.09 (m, 2H), 2.29 (s, 3H), 2.80 (t, J=6.5 Hz, 4H), 3.05 (s, 3H), 3.95 (dd, J=3.7, 13.9 Hz, 1H), 4.82 (dd, J=9.6, 13.9 Hz, 1H), 5.70 (dd, J=3.7, 9.6 Hz, 1H), 7.29-7.47 (m, 3H), 7.58 (m, 2H)

AP-MS (m/z): 425 (M⁺+1)

Example 144 Compound 151

In a manner similar to that in Example 133, Compound 151 (113 mg, 78%) was obtained from Compound 118 (100 mg, 0.305 mmol) prepared in Example 111, pyridine (0.062 mL, 0.76 mmol) and 4-bromobutyryl chloride (0.088 mL, 0.76 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.20 (m, 2H), 2.31 (s, 3H), 2.55 (t, J=6.9 Hz, 2H), 2.96 (s, 3H), 3.47 (t, J=6.2 Hz, 2H), 3.99 (dd, J=5.5, 13.9 Hz, 1H), 4.61 (dd, J=7.9, 13.9 Hz, 1H), 5.37 (dd, J=5.5, 7.9 Hz, 1H), 7.23-7.42 (m, 5H), 8.18 (s, 1H)

AP-MS (m/z): 476 (M⁻−1)

Example 145 Compound 152

Compound 151 (70 mg, 0.15 mmol) prepared in Example 144 was dissolved in N,N-dimethylformamide (1.8 mL). To the solution was added 60% sodium hydride (9 Mg, 0.2 mmol), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (chloroform/methanol=9/1) to obtain Compound 152 (51 mg, 88%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.20 (m, 2H), 2.35 (s, 3H), 2.57 (m, 2H), 2.95 (s, 3H), 3.93 (m, 2H), 3.99 (dd, J=5.5, 13.9 Hz, 1H), 4.61 (dd, J=8.1, 13.9 Hz, 1H), 5.33 (dd, J=5.5, 8.1 Hz, 1H), 7.25-7.44 (m, 5H)

AP-MS (m/z): 397 (M⁺+1)

Example 146 Compound 153

In a manner similar to that in Example 133, Compound 153 (120 mg, 80%) was obtained from Compound 118 (100 mg, 0.305 mmol) prepared in Example 111, pyridine (0.087 mL, 1.1 mmol) and 5-bromovaleryl chloride (0.143 mL, 1.07 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.75-1.98 (m, 4H), 2.31 (s, 3H), 2.36 (t, 7.0 Hz, 2H), 2.96 (s, 3H), 3.40 (t, J=6.2 Hz, 2H), 3.99 (dd, J=5.5, 13.9 Hz, 1H), 4.61 (dd, J=7.9, 13.9 Hz, 1H), 5.40 (dd, J=5.5, 7.9 Hz, 1H), 7.23-7.42 (m, 5H), 8.22 (s, 1H)

AP-MS (m/z): 491, 493 (M⁺+1)

Example 147 Compound 154

In a manner similar to that in Example 145, Compound 154 (36 mg, 72%) was obtained from Compound 153 (60 mg, 0.12 mmol) prepared in Example 146 and 60% sodium hydride (7 mg, 0.2 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.81-2.02 (m, 4H), 2.36 (s, 3H), 2.54 (m, 2H), 2.94 (s, 3H), 3.85 (m, 2H), 3.95 (dd, J=4.8, 13.8 Hz, 1H), 4.56 (dd, J=8.4, 13.8 Hz, 1H), 5.41 (dd, J=4.8, 8.4 Hz, 1H), 7.25-7.41 (m, 5H)

AP-MS (m/z): 411 (M⁺+1).

Example 148 Compound 155

In a manner similar to that in Example 133, Compound 155 (122 mg, 80%) was obtained from Compound 118 (99 mg, 0.30 mmol) prepared in Example 111, pyridine (0.061 mL, 0.75 mmol) and 6-bromohexanoyl chloride (0.115 mL, 0.754 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.40-1.77 (m, 4H), 1.87 (m, 2H), 2.31 (s, 3H), 2.35 (t, J=7.4 Hz, 2H), 2.96 (s, 3H), 3.40 (t, J=6.6 Hz, 2H), 3.99 (dd, J=5.4, 14.0 Hz, 1H), 4.60 (dd, J=7.9, 14.0 Hz, 1H), 5.36 (dd, J=5.4, 7.9 Hz, 1H), 7.20-7.43 (m, 5H), 8.06 (s, 1H)

AP-MS (m/z): 505, 507 (M⁺+1)

Example 149 Compound 156

In a manner similar to that in Example 145 , Compound 156 (17 mg, 32%) was obtained from Compound 155 (63 mg, 0.12 mmol) prepared in Example 148 and 60% sodium hydride (7 mg, 0.2 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 1.55-1.78 (m, 6H), 2.19 (s, 3H), 2.68 (m, 2H), 2.95 (s, 3H), 3.87 (dd, J=7.9, 13.7 Hz, 1H), 4.12 (m, 2H), 4.29 (dd, J=5.6, 13.7 Hz, 1H), 7.20-7.41 (m, 6H)

AP-MS (m/z): 425 (M⁺+1)

Example 150 Compound 157

Compound 99 (1.50 g, 3.21 mmol) prepared in Example 92 was dissolved in methanol (30 mL). To the solution was gradually added sodium borohydride (1.21 g, 32.0 mmol) at 50° C., and the mixture was stirred at the same temperature for 1.5 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=20/1) to obtain Compound 157 (0.26 g, 21%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.31 (s, 9H), 2.62 (m, 1H), 2.94 (s, 3H), 3.22 (m, 1H), 3.41 (m, 1H), 3.61 (m, 1H), 4.21 (s, 2H), 4.79 (m, 1H), 7.19-7.38 (m, 5H)

AP-MS (m/z): 385 (M⁺+1)

Example 151 Compound 158

In a manner similar to that in Example 133, Compound 158 (114 mg, 85%) was obtained from Compound 157 (97 mg, 0.25 mmol) prepared in Example 150, pyridine (0.051 mL, 0.63 mmol) and 4-bromobutyryl chloride (0.073 mL, 0.63 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.32 (s, 9H), 2.22 (m, 2H), 2.58 (t, J=7.4 Hz, 2H) 2.65 (m, 1H), 2.97 (s, 3H), 3.27 (m, 1H), 3.39 (m, 1H), 3.49 (t, J=6.2 Hz, 2H), 3.62 (m, 1H), 4.45 (br t, 1H), 7.21-7.39 (m, 5H), 8.00 (s, 1H)

AP-MS (m/z): 533, 535 (M⁺+1)

Example 152 Compound 159

In a manner similar to that in Example 145, Compound 159 (64 mg, 68%) was obtained from Compound 158 (110 mg, 0.206 mmol) prepared in Example 151 and 60% sodium hydride (12 mg, 0.31 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.34 (s, 9H), 2.23 (n, 2H), 2.56 (m, 2H), 2.61 (m, 1H), 2.97 (s, 3H), 3.27 (m, 1H), 3.40 (m, 1H), 3.63 (m, 1H), 3.98 (m, 2H), 4.01 (br t, J=3.5 Hz, 1H), 7.20-7.37 (m, 5H)

AP-MS (m/z): 453 (M⁺+1)

Example 153 Compound 160

Compound 119 (21 mg, 0.052 mmol) prepared in Example 112 was dissolved in a mixed solvent of toluene (1 mL) and tetrahydrofuran (1 mL). To the solution was added 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphethane-2,4-disulfide (Lawesson's reagent) (43 mg, 0.11 mmol), and the mixture was stirred at 90° C. for 5 hours. The reaction mixture was purified by preparative thin layer chromatography (chloroform/methanol=20/1) to obtain Compound 160 (15 mg, 67%).

¹NMR (270 MHz, CDCl₃) δ (ppm): 1.30 (s, 9H), 2.76 (s, 3H), 3.08 (s, 3H), 4.08 (dd, J=7.3, 13.8 Hz, 1H), 5.03 (t, J=7.3 Hz, 1H), 5.54 (dd, J=7.3, 13.8 Hz, 1H), 7.26-7.42 (m, 5H), 8.16 (s, 1H)

AP-MS (m/z): 429 (M⁺+1)

Example 154 Compound 161

In a manner similar to that in Example 100, Compound 161 (70 mg, 37%) was obtained from Compound 106 (0.165 g, 0.393 mmol) prepared in Example 99, oxalyl chloride (2 mL), 2-(methylamino)ethanol (295 mg, 3.93 mmol) and triethylamine (476 mg, 4.72 mmol).

AP-MS (m/z): 475 (M⁻−1)

Example 155 Compound 162

In a manner similar to that in Example 100, Compound 162 (135 mg, 68%) was obtained from Compound 106 (0.165 g, 0.393 mmol) prepared in Example 99, oxalyl chloride (2 mL) and diethanolamine (413 mg, 3.93 mmol).

AP-MS (m/z): 507 (M⁺+1)

Example 156 Compounds 163 and 164

In a manner similar to that in Example 100, Compound 163 (6.2 mg, 5%) and Compound 164 (36.1 mg, 31%) were obtained from Compound 106 (0.099 g, 0.237 mmol) prepared in Example 99, oxalyl chloride (1.25 mL) and 3-amino-1,2-propanediol (92 μL, 1.19 mmol).

Compound 163

AP-MS (m/z): 493 (M⁺+1)

Compound 164

AP-MS (m/z): 493 (M⁺+1)

Example 157 Compound 165

In a manner similar to that in Example 100, Compound 165 (37 mg, 33%) was obtained from Compound 115 (0.102 g, 0.236 mmol) prepared in Example 108, oxalyl chloride (1.25 mL) and 2-aminoethanol (144 mg, 2.36 mmol).

AP-MS (m/z): 477 (M⁺+1)

Example 158 Compound 166

Compound 105 (0.200 g, 0.461 mmol) prepared in Example 98 was dissolved in tetrahydrofuran (2 mL). To the solution was added lithium aluminium hydride (30 mg, 0.791 mmol) at 0° C., and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water and 30% aqueous sodium hydroxide. The insoluble precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (chloroform/methanol=9/1) to obtain Compound 166 (64.0 mg, 34%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.29 (s, 9H), 1.32 (s, 9H), 1.65 (m, 1H), 2.08 (m, 1H), 2.33 (m, 1H), 3.16 (m, 1H), 3.78 (m, 2H), 7.21-7.38 (m, 5H), 7.95 (br s, 1H)

AP-MS (m/z): 404 (M⁻−1)

Example 159 Compound 167

Compound 166 (0.0448 g, 0.110 mmol) prepared in Example 158 was dissolved in N,N-dimethylacetamide (0.5 mL). To the solution was added sulfamoyl chloride (51.1 mg, 0.442 mmol) at 0° C. with stirring, and the mixture was stirred at 0° C. for 20 minutes. After to the reaction mixture was added water, and the mixture was stirred. The deposited solid was collected by filtration, and dried under reduced pressure. The resulting solid was purified by preparative thin layer chromatography (chloroform/methanol=30/1) to obtain Compound 167 (30.2 mg, 57%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.29 (s, 9H), 1.33 (s, 9H), 1.89 (m, 1H), 2.14 (n, 1H), 2.38 (m, 1H), 3.32 (m, 1H), 4.28 (m, 1H), 4.43 (m, 1H), 5.08 (br s, 1H), 7.29 (m, 5H), 7.93 (br s, 1H)

AP-MS (m/z): 483 (M⁻−1)

Example 160 Compounds 168 and 169

Step 1: 2-Aminoacetophenone hydrochloride (4.56 g, 26.6 mmol) was dissolved in dichloromethane (250 mL). To the solution was added triethylamine (9.30 mL, 66.7 mmol), and the mixture was stirred at room temperature for 10 minutes. After the reaction mixture was cooled to 0° C., chloromethanesulfonyl chloride (purity 90%, 3.60 mL, 36.3 mmol) was added to the mixture, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added 2 mol/L hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added diethyl ether, and the deposited crystals were collected by filtration, and dried to obtain 2-(chloromethylsulfonylamino)acetophenone (5.00 g, 76%).

¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 4.67 (s, 2H), 4.94 (s, 2H), 7.54 (t, J=8.1 Hz, 2H), 7.67 (t, J=7.5 Hz, 1H), 7.97 (d, J=8.1 Hz, 2H), 8.01 (br s, 1H)

AP-MS (m/z): 247 (M⁺)

Step 2: 2-(Chloromethylsulfonylamino)acetophenone (1.00 g, 4.05 mmol) prepared above and thiosemicarbazide hydrochloride (1.03 g, 8.07 mmol) were dissolved in methanol (60 mL). To the solution was added concentrated hydrochloric acid (1.00 mL), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and to the residue was added ethyl acetate and saturated aqueous sodium hydrogencarbonate, and the mixture was subjected to separation. The organic layer was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/1 and 2/1) to obtain

2-(chloromethylsulfonylamino)acetophenone=thiosemicarbazone (0.51 g, 40%).

¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 4.17 (s, 2H), 4.93 (s, 2H), 7.37-7.42 (m, 3H), 7.52-7.56 (m, 2H), 8.13 (br s, 1H), 8.48 (br, 2H), 8.85 (br s, 1H)

AP-MS (m/z): 319 (M⁺)

Step 3: g-(Chloromethylsulfonylamino)acetophenone=thiosemicarbazone (7.48 g, 23.4 mmol) prepared above was dissolved in chloroform (250 mL). To the solution was added pyridine (11.4 mL, 141 mmol) and pivaloyl chloride (8.70 mL, 70.6 mmol), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added acetic anhydride (4.40 mL, 46.6 mmol), and the mixture was further stirred at room temperature for 15 hours. To the reaction mixture was added 2 mol/L hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/1 and 2/1) to obtain Compound 168 (3.56 g, 25%) and Compound 169 (1.77 g, 14%).

Compound 168

¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 1.16 (s, 9H), 2.23 (s, 3H), 4.00 (dd, J=11.3, 8.0 Hz, 1H), 4.47 (dd, J=11.3, 2.5 Hz, 1H), 4.91 (d, J=12.0 Hz, 1H), 4.97 (d, J=12.0 Hz, 1H), 7.28-7.39 (m, 5H), 8.10 (br s, 1H), 11.2 (br s, 1H)

AP-MS (m/z): 446 (M⁺)

Compound 169

¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 2.01 (s, 3H), 2.18 (s, 3H), 3.95 (d, J=14.3 Hz, 1H), 4.45 (d, J=14.3 Hz, 1H), 4.91 (d, J=12.0 Hz, 1H), 4.97 (d, J=12.0 Hz, 1H), 7.25-7.39 (m, 5H), 8.08 (br s, 1H), 11.6 (br s, 1H)

AP-MS (m/z): 404 (M⁺)

Example 161 Compounds 170 and 171

Step 1: 2-Aminoacetophenone hydrochloride (1.00 g, 5.85 mmol) was dissolved in dichloromethane (50 mL). To the solution was added triethylamine (2.50 mL, 17.9 mmol), and the mixture was stirred at room temperature for 10 minutes. After the reaction mixture was cooled to 0° C., chloroethanesulfonyl chloride (0.92 mL, 8.80 mmol) was added to the mixture, and the mixture was stirred at the same temperature for 15 minutes. To the reaction mixture was added 2 mol/L hydrochloric acid and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added a mixed solvent of ethyl acetate and n-hexane for crystallization to obtain 2-(vinylsulfonylamino)acetophenone (0.42 g, 32%).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 4.54 (d, J=4.5 Hz, 2H), 5.42 (br s, 1H), 5.94 (d, J=9.9 Hz, 1H), 6.28 (d, J=16.5 Hz, 1H), 6.53 (br dd, J=16.2, 9.9 Hz, 1H), 7.52 (t, J=7.5 Hz, 3H), 7.65 (t, J=7.8 Hz, 1H), 7.93 (t, J=5.1 Hz, 1H)

AP-MS (m/z): 225 (M⁺)

Step 2: 2-(Vinylsulfonylamino)acetophenone (0.32 g, 1.42 mmol) prepared above and thiosemicarbazide hydrochloride (0.27 g, 2.13 mmol) were dissolved in methanol (20 mL). To the solution was added concentrated hydrochloric acid (2 drops), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated. To the residue was added ethyl acetate and saturated aqueous sodium hydrogencarbonate, and the mixture was subjected to separation. The organic layer was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/1) to obtain 2-(vinylsulfonylamino)acetophenone=thiosemicarbazone (0.25 g, 58%).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 4.10 (s, 2H), 5.97 (d, J=9.9 Hz, 1H), 6.25 (d, J=16.8 Hz, 1H), 6.54 (dd, J=16.8, 9.9 Hz, 1H), 7.24-4.27 (m, 2H), 7.42 (br s, 1H), 7.52-7.53 (m, 3H), 7.81 (br s, 1H), 8.70 (m, 1H)

AP-MS (m/z): 297 (M⁺)

Step 3: 2-(Vinylsulfonylamino)acetophenone=thiosemicarbazone (0.25 g, 0.83 mmol) prepared above was dissolved in acetone (10 mL). To the solution was added pyridine (0.34 mL, 4.17 mmol) and pivaloyl chloride (0.31 mL, 2.50 mmol), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added acetic anhydride (0.16 mL, 1.66 mmol), and the mixture was further stirred for 3 days at room temperature. The reaction mixture was concentrated, and to the residue was added ethyl acetate and 2 mol/L hydrochloric acid, and the mixture was subjected to separation. The organic layer was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/1) to obtain Compound 170 (0.18 g, 52%) and Compound 171 (0.10 g, 26%).

Compound 170

¹H NMR (300 MHz, CDCl₃) δ (ppm): 1.27 (s, 9H), 2.31 (s, 3H), 3.87 (dd, J=13.4, 5.0 Hz, 1H), 4.45 (dd, J=13.4, 7.9 Hz, 1H), 5.57 (br s, 1H), 5.92 (d, J=9.9 Hz, 1H), 6.25 (d, J=16.5 Hz, 1H), 6.49 (dd, J=16.5, 9.9 Hz, 1H), 7.27-7.34 (m, 5H), 8.22 (br s, 1H)

AP-MS (m/z): 424 (M⁺)

Compound 171

¹H NMR (300 MHz, CDCl₃) δ (ppm): 1.29 (s, 9H), 1.33 (s, 9H), 3.85 (dd, J=13.5, 4.8 Hz, 1H), 4.49 (dd, J=13.5, 8.1 Hz, 1H), 5.29 (br s, 1H), 5.93 (br d, J=9.9 Hz, 1H), 6.27 (br d, J=16.5 Hz, 1H), 6.53 (br dd, J=16.4, 9.6 Hz, 1H), 7.27-7.34 (m, 5H), 8.06 (br s, 1H)

AP-MS (m/z): 466 (M⁺)

Example 162 Compound 172

Compound 170 (0.05 g, 0.11 mmol) prepared in Step 3 of Example 161 was dissolved in acetonitrile (3 mL). To the solution was added morpholine (0.10 mL), and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to obtain Compound 172 (0.04 g, 77%).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 1.27 (s, 9H), 2.33 (s, 3H), 2.42-2.45 (m, 4H), 2.78 (dquin, J=16.5, 6.0 Hz, 2H), 3.19 (t, J=6.6 Hz, 2H), 3.65-3.68 (m, 4H), 4.04 (dd, J=14.1, 4.8 Hz, 1H), 4.55 (dd, J=14.1, 7.5 Hz, 1H), 5.73 (br s, 1H), 7.30-7.38 (m, 5H), 8.05 (br s, 1H)

AP-MS (m/z): 511 (M⁺)

Example 163 Compound 173

In a manner similar to that in Example 162, Compound 173 (0.03 g, 66%) was obtained from Compound 170 (0.05 g, 0.11 mmol) prepared in Step 3 of Example 161 and 70% aqueous ethylamine (0.10 mL).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 1.10 (t, J=6.9 Hz, 3H), 1.27 (s, 9H), 2.32 (s, 3H), 2.65 (quin, J=7.2 Hz, 2H), 3.05-3.09 (m, 2H), 3.18-3.20 (m, 2H), 4.00 (d, J=13.5 Hz, 1H), 4.55 (d, J=13.8 Hz, 1H), 7.30-7.37 (m, 5H), 8.07 (br s, 1H)

AP-MS (m/z): 470 (M⁺+1)

Example 164 Compound 174

In a manner similar to that in Example 162, Compound 174 (0.03 g, 67%) was obtained from Compound 170 (0.05 g, 0.11 mmol) prepared in Step 3 of Example 161 and 2 mol/L dimethylamine methanol solution (0.10 mL).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 1.26 (s, 9H), 2.24 (s, 6H), 2.31 (s, 3H), 2.71-2.31 (m, 2H), 3.12-3.19 (m, 2H), 4.00 (d, J=13.5 Hz, 1H), 4.56 (d, J=13.5 Hz, 1H), 6.00 (br s, 1H), 7.31-7.36 (m, 5H), 8.06 (br s, 1H)

AP-MS (m/z): 469 (M⁺)

Example 165 Compound 175

In a manner similar to that in Example 162, Compound 175 (0.03 g, 52%) was obtained from Compound 170 (0.05 g, 0.11 mmol) prepared in Step 3 of Example 161 and 2-aminoethanol (0.10 mL).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 126 (s, 9H), 2.35 (s, 3H), 2.65-2.78 (m, 2H), 3.08-3.30 (m, 4H), 3.64 (t, J=5.1 Hz, 2H), 3.98 (d, J=13.5 Hz, 1H), 4.54 (d, J=13.5 Hz, 1H), 7.26-7.38 (m, 5H), 8.25 (br s, 1H)

AP-MS (m/z): 485 (M⁺)

Example 166 Compound 176

In a manner similar to that in Example 162, Compound 176 (0.01 g, 26%) was obtained from Compound 171 (0.05 g, 0.11 mmol) prepared in Step 3 of Example 161 and 70% aqueous ethylamine (0.10 mL).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 1.18 (m, 3H), 1.28 (s, 9H), 1.34 (s, 9H), 2.63 (quin, J=7.0 Hz, 2H), 2.73 (br q, J=6.3 Hz, 1H), 2.84 (br q, J=6.2 Hz, 1H), 3.18 (br t, J=6.6 Hz, 2H), 4.02 (d, J=13.2 Hz, 1H), 4.58 (d, J=13.2 Hz, 1H), 5.85 (br s, 1H), 7.27-7.35 (m, 5H), 8.02 (br s, 1H)

AP-MS (m/z): 512 (M⁺+1)

Example 167 Compound 177

In a manner similar to that in Example 162, Compound 177 (0.02 g, 39%) was obtained from Compound 171 (0.05 g, 0.11 mmol) prepared in Step 3 of Example 161 and 2 mol/L dimethylamine methanol solution (0.10 mL).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 1.28 (s, 9H), 1.34 (s, 9H), 2.25 (s, 6H), 2.73 (br q, J=6.3 Hz, 1H), 2.84 (br q, J=6.2 Hz, 1H), 3.18 (br t, J=6.6 Hz, 2H), 4.02 (d, J=13.2 Hz, 1H), 4.58 (d, J=13.2 Hz, 1H), 5.85 (br s, 1H), 7.27-7.35 (m, 5H), 8.02 (br s, 1H)

AP-MS (m/z): 512 (M⁺+1)

Example 168 Compound 178

In a manner similar to that in Example 11, Compound 178 (64.0 mg, 38%) was obtained from carbomethoxypropiophenone=thiosemicarbazone (0.144 g, 0.543 mol) prepared in Step 1 of Example 98, acetic anhydride (77 μL, 0.814 mmol) and pyridine (79 μL, 0.977 mmol).

¹H NMR (270 MHz,CDCl₃) δ (ppm): 2.13 (s, 3H), 2.20-2.70 (m, 4H), 3.61 (s, 3H), 6.52 (br s, 2H), 7.20-7.35 (m, 5H)

Example 169 Compound 179

In a manner similar to that in Example 15, Compound 179 (24.0 mg, 94%) was obtained from Compound 178 (0.0200 g, 0.0650 mol) prepared in Example 168, pivaloyl chloride (16 μL, 0.130 mmol) and pyridine (15 μL, 0.182 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.30 (s, 9H), 2.10 (s, 3H), 2.17-2.75 (m, 4H), 3.57 (s, 3H), 7.18-7.32 (m, 5H), 8.02 (br s, 1H)

AP-MS (m/z): 390 (M⁻−1)

Example 170 Compound 180

Compound 100 (304 mg, 0.0690 mmol) prepared in Example 93 and cerium chloride heptahydrate (257 mg, 0.690 mmol) were dissolved in methanol (800 mL). To the solution was gradually added sodium borohydride (522 mg, 13.8 mmol), and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure. To the residue was added 1 mol/L hydrochloric acid (100 mL), and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/acetone/ethyl acetate/n-hexane=9/1/1/1) to obtain Compound 180 (217 mg, 85%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.14 (t, J=7.0 Hz, 6H), 2.68 (m, 1H), 2.98 (s, 3H), 3.27 (m, 2H), 3.44 (m, 1H), 3.63 (m, 1H), 4.18 (br s, 2H), 4.51 (br s, 1H), 7.30 (m, 5H)

AP-MS (m/z): 371 (M⁺+1)

Example 171 Compound 181

In a manner similar to that in Example 15, Compound 181 (87.3 mg, 71%) was obtained from Compound 180 (100 mg, 0.270 mmol) prepared in Example 170, pyridine (65.4 μL, 0.810 mmol) and pivaloyl chloride (83.4 μL, 0.676 mmol).

AP-MS (m/z): 455 (M⁺+1)

Example 172 Compound 182

Compound 180 (60.6 mg, 0.170 mmol) obtained in Example 170 was dissolved in dichloromethane. To the solution was added pyridine (63.2 μL, 0.788 mmol) and 5-bromovaleryl chloride (23.0 μL, 0.172 mmol), and the mixture was stirred at room temperature for 5 hours. To the reaction mixture was added 1 mol/L hydrochloric acid and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in dimethyl sulfoxide (0.3 mL). To the solution was added sodium acetate (58.7 mg), and the mixture was stirred at 100° C. for 5 minutes. To the reaction mixture was added water (20 mL) and 1 mol/L hydrochloric acid (20 mL), and the mixture was extracted with chloroform. And then, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography, (chloroform/acetone/ethyl acetate/n-hexane=9/1/1/1) to obtain Compound 182 (42.5 mg, 45%).

AP-MS (m/z): 453 (M⁺+1)

Example 173 Compound 183

Compound 180 (100 mg, 0.270 mmol) prepared in Example 170 and pyridine (31.5 μL, 0.389 mmol) were dissolved in dichloromethane (2 mL). To the solution was added 4-bromobutyryl chloride (37.5 μL, 0.324 mmol) at 0° C., and the mixture was stirred at room temperature for 5 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added methanol (20 mL) and potassium carbonate (1.0 g), and the mixture was vigorously stirred at room temperature for 20 minutes. To the reaction mixture was added water and 1 mol/L hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform/acetone/ethyl acetate/n-hexane=9/1/1/1) to obtain Compound 183 (27.6 mg, 37%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.15 (d, J=6.6 Hz, 6H), 2.22 (m, 2H), 2.55-2.67 (m, 3H), 2.94 (s, 3H), 3.31-3.47 (m, 3H), 3.61 (m, 1H), 3.91-3.98 (m, 2H), 5.0 (br s, 1H), 7.20-7.35 (m, 5H)

AP-MS (m/z): 437 (M⁻−1)

Example 174 Compound 184

In a manner similar to that in Example 173, Compound 180 (84.1 mg, 0.227 mmol) prepared in Example 170 was treated with pyridine (88.0 μL, 1.09 mmol) and 5-bromovaleryl chloride (121 μL, 0.908 mmol), and then treated with methanol and potassium carbonate (1.0 g) to obtain Compound 184 (89.1 mg, 81%).

AP-MS (m/z): 485 (M⁺+1)

Example 175 Compound 185

In a manner similar to that in Step 3 of Example 92, Compound 185 (16.7 g, 85%) was obtained from 3-(methylaulfortylaraino)propiophenone=thiosemicarbazone (14.4 g, 47.9 mmol), propionyl chloride (16.7 mL, 192 mmol) and pyridine (18.6 mL, 230 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.12 (t, J=7.5 Hz, 3H), 1.19 (t, J=7.3 Hz, 3H), 2.37 (m, 2H), 2.63 (m, 3H), 2.96 (s, 3H), 3.35 (m, 2H), 3.58 (m, 1H), 4.55 (br s, 1H), 7.20-7.35 (m, 5H), 8.01 (br s, 1H)

Example 176 Compound 186

In a manner similar to that in Example 170, Compound 186 (11.7 g, 81%) was obtained from Compound 185 (16.7 g, 40.5 mmol) prepared in Example 175, cerium chloride heptahydrate (15.1 g, 40.5 mol) and sodium borohydride (12.8 g, 338 mol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.13 (t, J=8.7 Hz, 3H), 2.61-2.71 (m, 3H), 2.97 (s, 3H), 3.27-3.47 (m, 2H), 3.60-3.67 (m, 1H), 4.21 (br s, 2H), 4.65 (br s, 1H), 7.26-7.36 (m, 5H)

Example 177 Compound 187

In a manner similar to that in Example 15, Compound 187 (90.3 mg, 76%) was obtained from Compound 186 (96.0 mg, 0.269 mmol) prepared in Example 176, pyridine (65.4 μL, 0.810 mmol) and pivaloyl chloride (83.4 μL, 0.676 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.13 (t, J=6.0 Hz, 3H), 1.28 (s, 9H), 2.66 (m, 3H), 2.97 (s, 3H), 3.35 (m, 2H), 3.61 (m, 1H), 4.58 (br s, 1H), 7.32 (m, 5H), 8.08 (br s, 1H)

AP-MS (m/z): 441 (M⁺+1)

Example 178 Compound 188

In a manner similar to that in Example 172, Compound 188 (42.5 mg, 45%) was obtained from Compound 186 (100 mg, 0.221 mmol) prepared in Example 176, pyridine (85 μL, 1.05 mmol), 4-bromobutyryl chloride (110 μL, 0.949 mmol) and potassium carbonate (1.0 g).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.14 (t, J=7.5 Hz, 3H), 2.19 (m, 2H), 2.50-2.81 (m, 5H), 2.96 (s, 3H), 3.35 (m, 2H), 3.59 (m, 1H), 3.93 (m, 2H), 4.52 (br s, 1H), 7.20-7.34 (m, 5H)

AP-MS (m/z): 424 (M⁻−1)

Example 179 Compound 189

In a manner similar to that in Example 172, Compound 189 (27.6 mg, 37%) was obtained from Compound 186 (60.6 mg, 0.170 mmol) prepared in Example 176, pyridine (63.2 μL, 0.788 mmol), 5-bromovaleryl chloride (110 μL, 0.949 mmol) and potassium carbonate (1.0 g).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.14 (t, J=7.5 Hz, 3H), 1.79-1.99 (m, 4H), 2.54-2.75 (m, 5H), 2.96 (s. 3H), 3.19-3.27 (m, 2H), 3.57-3.68 (m, 1H), 3.83-3.95 (m, 2H), 4.36 (br s, 1H), 7.20-7.37 (m, 5H)

AP-MS (m/z): 439 (M⁺+1)

Example 180 Compound 190

In a manner similar to that in of Example 170, Compound 190 (86.5 mg, 0.248 mmol) was obtained from Compound 105 (1.01 g, 2.33 mmol) prepared in Example 98 and sodium borohydride (2.20 g, 58.2 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.30 (s, 9H), 2.37-2.46 (m, 1H), 2.63-2.86 (m, 2H), 3.41-3.51 (m, 1H), 3.71 (s, 3H), 4.09 (br s, 2H), 7.22-7.43 (m, 5H)

Example 181 Compound 191

Compound 191 (89.5 mg, 29%) was obtained in the same manner as that in Example 133 from Compound 190 (86.5 mg, 0.248 mmol) obtained in Example 180 and 4-bromobutyryl chloride (57 μL, 0.495 mmol).

AP-MS (m/z): 496 (M⁻−1)

Example 182 Compound 192

Compound 191 (89.5 mg, 0.18 mmol) prepared in Example 181 was dissolved in N,N-dimethylformamide (2.0 mL). To the solution was added 60% sodium hydride (14 mg, 0.359 mmol), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added acetic acid and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=2/1) to obtain Compound 192 (30.2 mg, 40%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.36 (s, 9H), 2.17-2.42 (m, 3H), 2.53-2.84 (m, 4H), 3.38-3.50 (s, 1H), 3.72 (s, 3H), 3.97 (m, 2H), 7.22-7.39 (m, 5H)

Example 183 Compound 193

In a manner similar to that in Example 99, Compound 193 (21.7mg, 74%) was obtained from Compound 192 (30.2 mg, 0.723 mmol) prepared in Example 182 and sodium hydroxide (8.7 mg, 0.217 mmol).

AP-MS (m/z): 402 (M⁻−1)

Example 184 Compound 194

In a manner similar to that in Example 100, Compound 194 (7.3 mg, 30%) was obtained from Compound 193 (21.7 mg, 0.054 mmol) prepared in Example 183, oxalyl chloride (0.25 ml) and 2-aminoethanol (16 μL, 26.9 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.34 (s, 9H), 2.17-2.28 (m, 3H), 2.54-2.82 (m, 2H), 3.34-3.46(m, 3H), 3.72 (dd, J=4.0, 6.0 Hz, 2H), 3.96 (br q, J=7.0 Hz, 2H), 7.32-7.34 (m, 5H)

Example 185 Compound 195

Step 1: In a manner similar to that in Step 1 of Example 1, 2-acetoxy-1-indanone=thiosemicarbazone (3.23 g, 57%) was obtained from 2-acetoxy-1-indanone (4.1 g, 21.6 mmol) and thiosemicarbazide hydrochloride (3.0 g, 23.7 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, 3-acetyl-6-aminospiro[1,3,4-thiadiazolin-2,1′-indan]-2′-yl acetate (187.4 mg, 48%) was obtained from 2-acetoxy-1-indanone=thiosemicarbazone (335.5 mg, 1.27 mmol) prepared above, pyridine (13 mL) and acetic anhydride (136 μL, 1.53 mmol)

Step 3: 3-Acetyl-5-aminospiro[1,3,4-thiadiazolin-2,1′-indan]-2′-yl acetate (163.8 mg) prepared above was dissolved in dichloromethane (2.0 mL). To the solution was added pyridine (520 μL, 6.44 mmol) and pivaloyl chloride (661 μL, 5.36 mmol), and the mixture was stirred at room temperature for 24 hours. To the reaction mixture was added water and chloroform, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/ethyl acetate=3/2) to obtain Compound 195 (118.0 mg, 57%) as a diastereoisomer mixture.

AP-MS (m/z): 390 (M⁺+1)

Example 186 Compound 196

Compound 195 (90.3 mg, 0.233 mmol) prepared in Example 185 was dissolved in methanol solution of 10% ammonia (4.8 mL), and the solution was allowed to stand at room temperature for 6 hours. The reaction mixture was concentrated, and then the residue was purified by silica gel column chromatography (chloroform/ethyl acetate=3/2) to obtain Compound 196 (16.6 mg, 20%) as a diastereoisomer mixture.

FAB-MS (m/z): 348 (M⁺+1)

Example 187 Compound 197

Step 1: In a manner similar to that in Step 1 of Example 1, 4-acetoxy-1-indanone=thiosemicarbazone (2.78 g, 80%) was obtained from 4-acetoxy-1-indanone (2.51 g, 13.2 mmol) and thiosemicarbazide hydrochloride (1.85 g, 14.5 mmol).

Step 2: In a manner similar to that in Example 11, Compound 197 (193.9 mg, 39%) was obtained from 4-acetoxy-1-indanone=thiosemicarbazone (364.5 mg, 1.38 mmol) prepared above, acetic anhydride (123 μL, 1.38 mmol) and pyridine (112 μL, 1.38 mmol).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 2.18 (s, 3H), 2.30 (s, 3H), 2.59-2.68 (m, 1H), 2.76-2.86 (m, 1H), 3.09-3.30 (m, 2H), 4.17 (br s, 2H), 6.99 (dd, J=7.7, 1.5 Hz, 1H), 7.31 (m, 2H)

Example 188 Compound 198

In a manner similar to that in Example 15, Compound 198 (136 mg, 98%) was obtained from Compound 197 (108.8 mg, 0.356 mmol) prepared in Example 187, pyridine (346 μL, 4.28 mmol) and pivaloyl chloride (439 μL, 3.56 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.34 (s, 9H), 2.18 (s, 3H), 2.29 (s, 3H), 2.56-2.63 (m, 1H), 2.79-2.92 (m, 1H), 3.08-3.22 (m, 2H), 6.98-7.03 (m, 1H), 7.28-7.31 (m, 2H), 8.08 (br s, 1H)

Example 189 Compound 199

In a manner similar to that in Example 186, Compound 199 (70.0 mg, 94%) was obtained from Compound 198 (83.1 mg,0.214 mmol) prepared in Example 188 and methanol solution of 10% ammonia (4.2 mL).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 1.34 (s, 9H), 2.21 (s, 3H), 2.58-2.67 (m, 1H), 2.81-2.91 (m, 1H), 3.07-3.27 (m, 2H), 5.25 (br s, 1H), 6.62 (d, J=7.7 Hz, 1H), 6.94 (d, J=7.7 Hz, 1H), 7.10 (t, J=7.7 Hz, 1H), 7.99 (br s, 1H)

Example 190 Tablets

Tablets comprising the following composition are obtained according to the conventional method.

Compound 1 5 mg Lactose 60 mg  Potato starch 30 mg  Polyvinyl alcohol 2 mg Magnesium stearate 1 mg Tar dye trace

INDUSTRIAL APPLICABILITY

The present invention provides a thiadiazoline derivative or a pharmacologically acceptable salt thereof which is useful for therapeutic treatment of a human malignant tumor, for example, breast cancer, gastric cancer, ovarian cancer, colon cancer, lung cancer, brain tumor, laryngeal cancer, hematological cancer, urinary or genital tumor including bladder cancer and prostatic cancer, renal cancer, skin carcinoma, hepatic carcinoma, pancreatic cancer, or uterine cancer, or the like. In addition, the present invention provides an antitumor agent comprising a thiadiazoline derivative or a pharmacologically acceptable salt thereof as an active ingredient. 

1. A method of treating hematological cancer in a human in need thereof comprising administering an effective amount of a compound represented by formula (99), (187), (181), (188), (176), or (177),

or a pharmacologically acceptable salt thereof.
 2. The method according to claim 1, wherein the compound is a compound represented by formula (176),

or a pharmacologically acceptable salt thereof. 